Purine derivatives having phosphodiesterase iv inhibition activity

ABSTRACT

Disclosed are compounds of the formula:whereinR3, R6a, R6b and R8 are substituted as disclosed herein. The compounds are effective in effecting PDE IV inhibition in patients in need thereof.

This application is a continuation-in-part of U.S. Ser. No. 09/285,473,filed Apr. 2, 1999, the disclosure of which is herein incorporated byreference.

BACKGROUND OF THE INVENTION

Asthma is a complex disease involving the concerted actions of multipleinflammatory and immune cells, spasmogens, inflammatory mediators,cytokines and growth factors. In recent practice there have been fourmajor classes of compounds used in the treatment of asthma, namelybronchodilators (e.g., β-adrenoceptor agonists), anti-inflammatoryagents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g.,cromolyn sodium) and xanthines (e.g., theophylline) which appear topossess both bronchodilating and anti-inflammatory activity.

Theophylline has been a preferred drug of first choice in the treatmentof asthma. Although it has been touted for its direct bronchodilatoryaction, theophylline's therapeutic value is now believed to also stemfrom anti-inflammatory activity. Its mechanism of action remainsunclear. However, it is believed that several of its cellular activitiesare important in its activity as an anti-asthmatic, including cyclicnucleotide phosphodiesterase inhibition, adenosine receptor antagonism,stimulation of catecholamine release, and its ability to increase thenumber and activity of suppressor T-lymphocytes. While all of these mayactually contribute to its activity, only PDE inhibition may account forboth the anti-inflammatory and bronchodilatory components. However,theophylline is known to have a narrow therapeutic index and a widerange of untoward side effects which arc considered problematic.

Of the activities mentioned above, theophylline's activity in inhibitingcyclic nucleotide phosphodiesterase has received considerable attentionrecently. Cyclic nucleotide phosphodiesterases (PDEs) have receivedconsiderable attention as molecular targets for anti-asthmatic agents.Cyclic 3′,5′-adenosine monophosphate (cAMP) and cyclic 3′,5′-guanosinemonophosphate (cGMP) are known second messengers that mediate thefunctional responses of cells to a multitude of hormones,neurotransmitters and autocoids. At least two therapeutically importanteffects could result from phosphodiesterase inhibition, and theconsequent rise in intracellular adenosine 3′,5′-monophosphate (cAMP) orguanosine 3′,5′-monophosphate (CGMP) in key cells in the pathophysiologyof asthma. These are smooth muscle relaxation (resulting inbronchodilation) and anti-inflammatory activity.

It has become known that there are multiple, distinct PDE isoenzymeswhich differ in their cellular distribution. A variety of inhibitorspossessing a marked degree of selectivity for one isoenzyme or the otherhave been synthesized.

The structure-activity relationships (SAR) of isozyme-selectiveinhibitors has been discussed in detail, e.g., in the article ofTheodore J. Torphy, et al., “Novel Phosphodiesterase Inhibitors For TheTherapy Of Asthma”, Drug News & Prospectives, 6(4) May 1993, pages203-214. The PDE enzymes can be grouped into five families according totheir specificity toward hydrolysis of cAMP or cGMP, their sensitivityto regulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. PDE I is stimulated by Ca²⁺/calmodulin.PDE II is cGMP-stimulated, and is found in the heart and adrenals. PDEIII is cGMP-inhibited, and inhibition of this enzyme creates positiveinotropic activity. PDE IV is cAMP specific, and its inhibition causesairway relaxation, antiinflammatory and antidepressant activity. PDE Vappears to be important in regulating cGMP content in vascular smoothmuscle, and therefore PDE V inhibitors may have cardiovascular activity.

While there are compounds derived from numerous structure activityrelationship studies which provide PDE III inhibition, the number ofstructural classes of PDE IV inhibitors is relatively limited. Analoguesof rolipram, which has the following structural formula (A):

and of RO-20-1724, which has the following structural formula (B):

have been studied.

U.S. Pat. No. 4,308,278 discloses compounds of the formula (C)

wherein R₁ is (C₃-C₆)cycloalkyl or benzyl; each of R₂ and R₃ is hydrogenor (C₁-C₄)alkyl; R₄ is R₂ or alkoxycarbonyl; and R₅ is hydrogen oralkoxycarbonyl.

Compounds of Formula (D) are disclosed in U.S. Pat. No. 3,636,039. Thesecompounds are benzylimidazolidinones which act as hypertensive agents.

Substituents R₁-R₄ in Formula D represent a variety of groups, includinghydrogen and lower alkyl.

PCT publication WO 87/06576 discloses antidepressants of Formula E:

wherein R₁ is a polycycloalkyl group having from 7 to 11 carbon atoms R₂is methyl or ethyl; X is O or NH; and Y comprises a mono- or bicyclicheterocyclic group with optional substituents.

Rolipram, which was initially studied because of its activity as ananti-depressant, has been shown to selectively inhibit the PDE IV enzymeand this compound has since become a standard agent in theclassification of PDE enzyme subtypes. There appears to be considerabletherapeutic potential for PDE IV inhibitors. Early work focused ondepression as a CNS therapeutic endpoint and on inflammation, and hassubsequently been extended to include related diseases such as dementiaand asthma. In-vitro, rolipram, RO20-1724 and other PDE IV inhibitorshave been shown to inhibit (1) mediator synthesis/release in mast cells,basophils, monocytes and eosinophils; (2) respiratory burst, chemotaxisand degranulation in neutrophils and eosinophils; and (3)mitogen-dependent growth and differentiation in lymphocytes (The PDE IVFamily Of Calcium-Phosphodiesterases Enzymes, John A. Lowe, III, et al.,Drugs of the Future 1992, 17(9):799-807).

PDE IV is present in all the major inflammatory cells in asthmaincluding eosinophils, neutrophils, T-lymphocytes, macrophages andendothelial cells. Its inhibition causes down regulation of inflammatorycell activation and relaxes smooth muscle cells in the trachea andbronchus. On the other hand, inhibition of PDE III, which is present inmyocardium, causes an increase in both the force and rate of cardiaccontractility. These are undesirable side effects for ananti-inflammatory agent. Theophylline, a non-selective PDE inhibitor,inhibits both PDE III and PDE IV, resulting in both desirableanti-asthmatic effects and undesirable cardiovascular stimulation. Withthis well-known distinction between PDE isozymes, the opportunity forconcomitant anti-inflammation and bronchodilation without many of theside effects associated with theophylline therapy is apparent. Theincreased incidence of morbidity and mortality due to asthma in manyWestern countries over the last decade has focused the clinical emphasison the inflammatory nature of this disease and the benefit of inhaledsteroids. Development of an agent that possesses both bronchodilatoryand antiinflammatory properties would be most advantageous.

It appears that selective PDE IV inhibitors should be more effectivewith fewer side effects than theophylline. Clinical support has beenshown for this hypothesis. Furthermore, it would be desirable to providePDE IV inhibitors which are more potent and selective than rolipram andtherefore have a lower IC₅₀ so as to reduce the amount of the agentrequired to effect PDE IV inhibition.

In recent years, several different compounds have been suggested aspossible therapeutic compositions which achieve the desired PDE IVinhibition without the side effects alluded to above. However, theseefforts have been chiefly directed to developing non-specificderivatives of particular classes of compounds, i.e. rolipram analogs,benzoxazoles, adenines, thioxanthines, etc. These efforts, however, haveresulted in a myriad of compounds having a wide range of PDE IV IC₅₀'s.Often, the general formulas disclosed yield several compounds which havepoor levels of PDE IV inhibition and/or lack sufficient specificity.Consequently, these efforts often provide no assurance that anyparticular derivative within the formula will have the desiredcombination of high PDE IV inhibition and selectivity.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of the present invention to provide newcompounds which are more effective selective PDE IV inhibitors thanknown prior art compounds.

It is another object of the present invention to provide new compoundswhich act as effective PDE IV inhibitors with lower PDE III inhibition.

It is another object of the present invention to provide methods fortreating a patient requiring PDE IV inhibition.

It is another object of the present invention to provide new compoundsfor treating disease states associated with abnormally highphysiological levels of inflammatory cytokines, including tumor necrosisfactor.

It is another object of the present invention to provide a method ofsynthesizing the new compounds of this invention.

It is another object of the present invention to provide a method fortreating a patient suffering from disease states such as asthma;allergies; inflammation; depression, dementia, including Alzheimer'sdisease, vascular dementia, and multi-in-farct dementia; a diseasecaused by Human Immunodeficiency Virus; and disease states associatedwith abnormally high physiological levels of inflammatory cytokines.

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof With the aboveand other objects in view, the present invention comprises compoundshaving the general formula (I):

wherein

R³ is selected from the group consisting of

hydrogen;

C₁₋₁₀alkyl which is unbranched or branched and is optionally substitutedwith 1-3 substituents chosen from the group consisting of OH,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H, ═O orbenzyloxy, said benzyloxy optionally substituted with 1-3 substituentschosen from the group consisting of halogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy;

C₂₋₁₀alkenyl which is unbranched or branched and is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H or ═O

C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen,halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H or ═O;

aryl which is optionally substituted with 1-3 substituents chosen fromthe group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino,carbamyl, amido, C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀acylamino,C₁₋₁₀alkylsulfonylamino, C═NOH, C═NOCONR₂, phenyl or benzyl

ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substituted with 1-3substituents chosen from the group consisting of carboxy,C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀)alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy,C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy orC₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy optionally substituted inone position at the alkyl moiety with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀alkyl; and wherein the alkyl moiety ofsaid ar (C₁₋₄)alkyl is optionally substituted with OH, halogen,C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;

heterocyclyl which is optionally substituted on the carbons or nitrogensof the ring with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl;

heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl, and wherein said alkyl moiety is optionallysubstituted with OH, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, C₃₋₁₂cycloalkyl,halogen or halo(C₁₋₁₀)alkyl;

heteroaryl, which is optionally substituted with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen,nitro, CF₃, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy or oxo; and

heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, trihalocarbon, C₁₋₁₀alkoxyor C₃₋₁₂cycloalkoxy;

R⁸ is selected from the group consisting of

hydrogen;

C₁₋₁₀alkyl which is unbranched or branched and is optionally substitutedwith 1-3 substituents chosen from the group consisting of OH,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H, ═O orbenzyloxy, said benzyloxy optionally substituted with 1-3 substituentschosen from the group consisting of halogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy;

C₂₋₁₀alkenyl which is unbranched or branched and is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkyl which is optionally substituted with 1-3 substituentschosen from the group. consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen,halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H or ═O;

aryl which is optionally substituted with 1-3 substituents chosen fromthe group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino,carbamyl, amido, C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀acylamino,C₁₋₁₀alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl;

ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substituted with 1-3substituents chosen from the group consisting of carboxy,C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀)alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy,C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy orC₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy optionally substituted inone position at the alkyl moiety with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀alkyl and wherein the alkyl moiety ofsaid ar (C₁₋₄)alkyl is optionally substituted with OH, halogen,C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;

heterocyclyl which is optionally substituted on the carbons or nitrogensof the ring with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl;

heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl, and wherein said alkyl moiety is optionallysubstituted with OH, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, C₃₋₁₂cycloalkyl,halogen or halo(C₁₋₁₀)alkyl;

heteroaryl, which is optionally substituted with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen,nitro, CF₃, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy or oxo; and

heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, trihalocarbon, C₁₋₁₀alkoxyor C₃₋₁₂cycloalkoxy;

R^(6a) and R^(6b) are independently selected from the group consistingof

hydrogen;

C₁₋₁₀alkyl which is unbranched or branched and is optionally substitutedwith 1-3 substituents chosen from the group consisting of OH,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H, ═O orbenzyloxy, said benzyloxy optionally substituted with 1-3 substituentschosen from the group consisting of halogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy,

C₂₋₁₀alkenyl which is unbranched or branched and is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H or ═O;

C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH, NOCONH₂,CO₂H or ═O;

C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen,halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H or ═O;

aryl which is optionally substituted with 1-3 substituents chosen fromthe group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino,carbamyl, amido, C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀acylamino,C₁₋₁₀alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl;

ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substituted with 1-3substituents chosen from the group consisting of carboxy,C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀)alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy,C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy orC₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy optionally substituted inone position at the alkyl moiety with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀alkyl; and wherein the alkyl moiety ofsaid ar (C₁₋₄)alkyl is optionally substituted with OH, halogen,C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;

heterocyclyl which is optionally substituted on the carbons or nitrogensof the ring with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl;

heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl and wherein said alkyl moiety is optionallysubstituted with OH, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, C₃₋₁₂cycloalkyl,halogen or halo(C₁₋₁₀)alkyl;

heteroaryl, which is optionally substituted with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen,nitro, CF₃, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy or oxo; and

heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, trihalocarbon, C₁₋₁₀alkoxyor C₃₋₁₂cycloalkoxy;

provided that when R³ is an unsubstituted benzyl group, R^(6a) is amethyl or isopropyl group and R^(6b) is a hydrogen atom;

when R³, R^(6a) and R^(6b) are methyl groups, then R⁸ is other than ahydrogen atom;

when R⁸ is methyl or a hydrogen atom, R³ is nether methyl or hydrogen;

when R⁸ is phenyl, R³ is not methyl;

when R⁸ is pyridyl, R³ is not a hydrogen atom; and

when R^(6a) and R^(6b) are both hydrogen, then R⁸ is not hydrogen oralkylC(O)OH;

and pharmaceutically acceptable salts thereof.

In certain preferred embodiments, R³ is an ar(C₁₋₄)alkyl, wherein thearyl moiety is optionally substituted at 1-3 positions with halogen,nitro, alkoxy, cycloalkoxy or CF₃, and wherein the alkyl moiety isoptionally substituted with OH, halogen, alkoxy and cycloalkoxy. Thearalkyl may be a benzyl, which may be optionally substituted asdescribed above. In other preferred embodiments, the aralkyl is a benzylsubstituted with alkoxy and cycloalkoxy.

In other preferred embodiments, R^(6a) is a hydrogen. In other preferredembodiments, R^(6a) is hydrogen and R^(6b) is selected from the groupconsisting of C₁₋₁₀alkyl, preferably C₁₋₈alkyl, which is unbranched orbranched and is optionally substituted with OH, alkoxy, cycloalkoxy,halogen, ═NOH, ═NOCONH₂, CO₂H or ═O; C₂₋₁₀alkenyl which is unbranched orbranched and is optionally substituted with OH, alkoxy, cycloalkoxy,halogen, ═NOH, ═NOCONH₂, CO₂H or ═O; C₃₋₁₀cycloalkyl, preferablyC₃₋₈cycloalkyl, which is optionally substituted with OH, alkoxy,cycloalkoxy, halogen, haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O;C₃₋₁₀cycloalkenyl which is optionally substituted with OH, alkoxy,cycloalkoxy, halogen, haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O; aryl whichis optionally substituted with C₁₋₈alkyl, OH, halogen, alkoxy,cycloalkoxy, NH₂, alkylamino, dialkylamino, carbamyl, amido,C₁₋₈alkylamido, C₁₋₃dialkylamido, C₁₋₈acylamino, C₁₋₈alkylsulfonylamino,C═NOH, C═NOCONH₂, phenyl or benzyl; aralkyl C₁₋₄ wherein the aryl moietyis optionally substituted with halogen, nitro, alkoxy, cycloalkoxy orCF₃, and wherein the alkyl moiety is optionally substituted with OH,halogen, alkoxy and cycloalkoxy; heterocyclyl which is optionallysubstituted on the carbons or nitrogens of the ring with C₁₋₈alkyl, OH,halogen, alkoxy, cycloalkoxy, NH2, alkylamino, dialkylamino, carbamyl,amido, C₁₋₈alkylamido, C₁₋₃dialkylamido, C₁₋₈acylamino,C₁₋₈alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl; andheterocyclylalkyl (C₁-C₄) wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with C₁₋₈alkyl, OH,halogen, alkoxy, cycloalkoxy, NH₂, alkylamino, dialkylamino, carbamyl,amido, C₁₋₈alkylamido, C₁₋₃dialkylamido, C₁₋₈acylamino,C₁₋₈alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl, and whereinsaid alkyl moiety is optionally substituted with OH, alkoxy,cycloalkoxy, halogen or haloalkyl; heteroaryl, which is optionallysubstituted with C₁₋₄alkyl, halogen, nitro, CF₃, alkoxy or cycloalkoxy;and heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with C₁₋₄alkyl, halogen, nitro, CF₃, alkoxy or cycloalkoxy;

In other preferred embodiments, R^(6a) is hydrogen and R^(6b) isselected from the group consisting of C₁₋₁₀alkyl, preferably C₁₋₈alkyl,which is unbranched or branched and is optionally substituted with OH,alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H or ═O; C₂₋₁₀alkenylwhich is unbranched or branched and is optionally substituted with OH,alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H or ═O;C₃₋₁₀cycloalkyl, preferably C₃₋₈cycloalkyl, which is optionallysubstituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, ═NOH,═NOCONH₂, CO₂H or ═O; and C₃₋₁₀cycloalkenyl, which is optionallysubstituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl, ═NOH,═NOCONH₂, CO₂H or ═O. In particular, R^(6a) may be a hydrogen and R^(6b)may be a C₁₋₈alkyl which is unbranched or branched and is optionallysubstituted with OH, alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂Hor ═O. In other preferred embodiments of the invention, R^(6b), N, andR^(6a) form a 3 to 8 membered ring containing at least one carbon atom,from one to three nitrogen atoms, from zero to two oxygen atoms, andfrom zero to two sulfur atoms, optionally substituted with hydroxy,alkoxy, cycloalkoxy, C₁₋₄alkyl, CO₂H, CONH₂, ═NOH, ═NOCONH₂, ═O.

In other preferred embodiments, R⁸ is selected from the group consistingof C₁₋₁₀alkyl, preferably C₁₋₈alkyl, which is unbranched or branched andis optionally substituted with OH, alkoxy, cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H or ═O; C₂₋₁₀alkenyl, which is unbranched or branched andis optionally substituted with OH, alkoxy, cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H or ═O; C₃₋₁₀cycloalkyl, preferably C₃₋₈cycloalkyl, whichis optionally substituted with OH, alkoxy, cycloalkoxy, halogen,haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O; C₃₋₁₀cycloalkenyl, which isoptionally substituted with OH, alkoxy, cycloalkoxy, halogen, haloalkyl,═NOH, ═NOCONH₂, CO₂H or ═O; C₄₋₈cycloalkylalkyl wherein the cycloalkylportion is optionally substituted with OH, alkoxy, cycloalkoxy, halogen,haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O; aryl which is optionallysubstituted with C₁₋₈alkyl, OH, halogen, alkoxy, cycloalkoxy, NH₂,alkylamino, dialkylamino, carbamyl, amido, C₁₋₈alkylamido,C₁₋₃dialkylamido, C₁₋₈acylamino, C₁₋₈alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl or benzyl; aralkyl C₁₋₄ wherein the aryl moiety isoptionally substituted with hydroxy, halogen, nitro, alkoxy, cycloalkoxyor CF₃, and wherein the alkyl moiety is optionally substituted with OH,halogen, alkoxy and cycloalkoxy; heterocyclyl which is optionallysubstituted on the carbons or nitrogens of the ring with C₁₋₈alkyl OH,halogen, alkoxy, cycloalkoxy, NH₂, alkylamino, dialkylamino, carbamyl,amido, C₁₋₈alkylamido, C₁₋₃dialkylamido, C₁₋₈acylamino,C₁₋₈alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl;heterocyclylalkyl (C₁-C₄) wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with C₁₋₈alkyl, OH,halogen, alkoxy, cycloalkoxy, NH₂, alkylamino, dialkylamino, carbamyl,amido, C₁₋₈alkylamido, C₁₋₃dialkylamido, C₁₋₈acylamino,C₁₋₈alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl or benzyl, and whereinsaid alkyl moiety is optionally substituted with OH, alkoxy,cycloalkoxy, halogen or haloalkyl; heteroaryl, which is optionallysubstituted with C₁₋₄alkyl, halogen, nitro, CF₃, alkoxy or cycloalkoxy;and heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with C₁₋₄alkyl, halogen, nitro, CF₃, alkoxy or cycloalkoxy.

In other preferred embodiments, R⁸ is selected from the group consistingof C₁₋₈alkyl which is unbranched or branched and is optionallysubstituted with OH, alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONF₂, CO₂Hor ═O; and C₃₋₈cycloalkyl which is optionally substituted with OH,alkoxy, cycloalkoxy, halogen, haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O.

In other preferred embodiments of the invention R³, R^(6a), R^(6b) andR⁸ are selected from the group consisting of A and B,

wherein A is selected from the group consisting of

hydrogen;

C₁₋₁₀alkyl which is unbranched or branched and is optionally substitutedwith 1-3 substituents chosen from the group consisting of OH,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H, ═O andbenzyloxy; said benzyloxy optionally substituted with 1-3 substituentschosen from the group consisting of halogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy;

C₂₋₁₀alkenyl which is unbranched or branched and is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H and ═O;

C₃₋₁₀cycloalkyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O;

C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O;

C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen,halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O,

aryl which is optionally substituted with 1-3 substituents chosen fromthe group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino,carbamyl, amido, C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀acylamino,C₁₋₁₀alkylsulfonylamino, C═NOH, C═NOCONH₂, phenyl and benzyl;

ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substituted with 1-3substituents chosen from the group consisting of carboxy,C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀)alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy,C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy andC₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy optionally substituted inone position at the alkyl moiety with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀alkyl; and wherein the alkyl moiety ofsaid ar (C₁₋₄)alkyl is optionally substituted with OH, halogen,C₁₋₁₀alkoxy or C₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;

heterocyclyl which is optionally substituted on the carbons or nitrogensof the ring with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl and benzyl;

heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, carbamyl, amido, C₁₋₁₀alkylamido,C₁₋₁₀dialkylamido, C₁₋₁₀acylamino C₁₋₁₀alkylsulfonylamino, C═NOH,C═NOCONH₂, phenyl and benzyl, and wherein said alkyl moiety isoptionally substituted with OH, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy,C₃₋₁₂cycloalkyl, halogen and halo(C₁₋₁₀)alkyl;

heteroaryl, which is optionally substituted with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen,nitro, CF₃, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy and oxo; and

heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, trihalocarbon, C₁₋₁₀alkoxyand C₃₋₁₂cycloalkoxy; and

B is selected from the group consisting of

C₁₋₁₀alkyl which is unbranched or branched and is substituted with 1-3substituents chosen from the group consisting of benzyloxy,methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy,thienylmethoxy and alkylamino; said substituents optionally substitutedwith 1-3 substituents chosen from the group consisting of halogen,C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy and oxo; saidsubstituted C₁₋₁₀alkyl further optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀alkoxy,C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H, and ═O

C₂₋₁₀alkenyl which is unbranched or branched and is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H and ═O;

C₃₋₁₀cycloalkyl which is substituted with 1-3 substituents chosen fromthe group consisting of C₁₋₁₀alkyl and C₃₋₁₂cycloalkyl; said substitutedC₃₋₁₀cycloalkyl further optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy,halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O;

C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O;

C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion issubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, halo(C₁₋₁₀)alkyl, and ═O saidsubstituted C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl further optionally substitutedwith 1-3 substituents chosen from the group consisting of OH,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, ═NOH, ═NOCONH₂, and CO₂H;

aryl which is substituted with 1-3 substituents chosen from the groupconsisting of carbamyl, amido, C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido,C₁₋₁₀acylamino and C₁₋₁₀alkylsulfonylamino; said substituted arylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino,C═NOH, C═NOCONH₂, phenyl and benzyl;

ar(C₁₋₄)alkyl wherein the aryl moiety is substituted with 1-3substituents chosen from the group consisting of carboxy,C₁₋₁₀alkylcarboxy, hydroxy(C₁₋₁₀)alkoxy, nitro, benzyloxy, heterocyclyl,C₁₋₁₀cycloalkyl(C₃₋₁₂)alkyloxy, ar(C₁₋₁₀)alkyloxy, aryloxy,amino(C₁₋₁₀)alkoxy, C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy,heteroar(C₁₋₁₀)alkyloxy, heterocyclyloxy, C₁₋₁₀alkoxy andC₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy substituted in oneposition at the alkyl moiety with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀alkyl and wherein the alkyl moiety ofsaid ar (C₁₋₄)alkyl is optionally substituted with OH, halogen,C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;and said substituted ar(C₁₋₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of halogen, hydroxy,trihalocarbon, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy andC₃₋₁₂cycloalkoxy

heterocyclyl which is substituted on the carbons or nitrogens of thering with 1-3 substituents chosen from the group consisting of carbamyl,C₁₋₁₀acylamino and C₁₋₁₀alkylsulfonylamino; said substitutedheterocyclyl further optionally substituted with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀alkyl, OH, halogen, C₁₋₁₀alkoxy,C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, amido,C₁₋₁₀alkylamido, C₁₋₁₀dialkylamido, C═NOH, C═NOCONHR, phenyl and benzyl;

heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is substitutedon the carbons or nitrogens of the ring with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀acylamino, C₁₋₁₀alkylsulfonylamino,and C₁₋₁₀alkyl, said C₁₋₁₀alkyl substituted with OH, C₁₋₁₀alkoxy,C₃₋₁₂cycloalkoxy, C₃₋₁₂cycloalkyl, halogen or halo(C₁₋₁₀)alkyl; saidsubstituted heterocyclyl(C₁-C₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, NH₂,C₁₋₁₀alkylamino, C₁₋₁₀dialkylamino, amido, C₁₋₁₀alkylamido andC₁₋₁₀dialkylamido,

heteroaryl, which is substituted with oxo; said substituted heteroarylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃,C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy; and

heteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is substituted withnitro; said heteroaryl(C₁₋₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, halogen, trihalocarbon, C₁₋₁₀alkoxy andC₃₋₁₂cycloalkoxy; and

provided that at least one of R³, R^(6a), R^(6b) and R⁸ is B.

In certain preferred embodiments, R³ is A and is ar(C₁₋₄)alkyl,preferably benzyl, wherein the aryl moiety is optionally substitutedwith 1-3 substituents chosen from the group consisting of halogen,nitro, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy or CF₃, and wherein the alkylmoiety is optionally substituted with 1-3 substituents chosen from thegroup consisting of OH, halogen, C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy. Whenthe ar(C₁₋₄)alkyl is benzyl, said aryl moiety is preferably substitutedwith with cyclopentyloxy and methoxy.

In certain preferred embodiments, R^(6a) is A and is hydrogen.

In certain preferred embodiments R^(6b) is A and is selected from thegroup consisting of

hydrogen;

C₁₋₈alkyl which is unbranched or branched and is optionally substitutedwith OH, alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H or ═O; and

C₃₋₈cycloalkyl which is optionally substituted with OH, alkoxy,cycloalkoxy, halogen, haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O.

In certain preferred embodiments R⁸ is B and is selected from the groupconsisting of

C₁₋₁₀alkyl which is unbranched or branched and is substituted with 1-3substituents chosen from the group consisting of benzyloxy,methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy,thienylmethoxy and alkylamino, said substituents optionally substitutedwith 1-3 substituents chosen from the group consisting of halogen,C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy and oxo.

In certain preferred embodiments R³ is A and is ar(C₁₋₄)alkyl,preferably benzyl, wherein the aryl moiety is optionally substitutedwith 1-3 substituents chosen from the group consisting of halogen,nitro, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy or CF₃, and wherein the alkylmoiety is optionally substituted with 1-3 substituents chosen from thegroup consisting of OH, halogen, C₁₋₁₀alkoxy and C₃₋₁₂cycloalkoxy andwhen the ar(C₁₋₄)alkyl is benzyl, said aryl moiety is preferablysubstituted with with cyclopentyloxy and methoxy; R^(6a) is A and ishydrogen; R^(6b) is A and is selected from the group consisting ofhydrogen, C₁₋₈alkyl which is unbranched or branched and is optionallysubstituted with OH, alkoxy, cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂Hor ═O; and C₃₋₈cycloalkyl which is optionally substituted with OH,alkoxy, cycloalkoxy, halogen, haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O; andR⁸ is B and is selected from the group consisting of C₁₋₁₀alkyl which isunbranched or branched and is substituted with 1-3 substituents chosenfrom the group consisting of benzyloxy, methylenedioxybenzyloxy,methylenedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino,said substituents optionally substituted with 1-3 substituents chosenfrom the group consisting of halogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy and oxo.

Certain preferred adenine compounds according to the invention include:6-ethylamino-3-hexyl-3H-purine; 3-hexyl-6-methylamino-3H-purine;8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine;8-cyclopropyl-3-ethyl-6-propylamino-3H-purine;8-cyclopropyl-3-ethyl-6-methylamino-3H-purine;3-butyl-6-ethylamino-3H-purine;3-butyl-8-cyclopropyl-6-ethylamino-3H-purine;6-ethylamino-3-propyl-3H-purine;8-cyclopropyl-6-ethylamino-3-propyl-3H-purine;8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine;3-benzyl-6-ethylamino-3H-purine;8-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine;3-(2-methylbutyl)-6-(2-(piperazine-1-yl)ethylamino)-3H-purine;3-cyclohexylmethyl-6-ethylamino-3H-purine;3-benzyl-6-ethylamino-8-(1-methylethyl)-3H-purine;3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-purine;3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine;3-ethyl-8-isopropyl-6-benzylamino-3H-purine;3-ethyl-8-isopropyl-6-ethylamino-3H-purine;3-ethyl-8-cyclopentyl-6-benzylamino-3H-purine;3-ethyl-8-cyclopentyl-6-ethylamino-3H-purine;3-(4-chlorobenzyl)-6-ethylamino-3H-purine;3-(2-chlorobenzyl)-6-ethylamino-3H-purine;3-(2-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine;6-benzylamino-8-cyclopropyl-3-propyl-3H-purine;8-cyclopropyl-6-hexylamino-3-propyl-3H-purine;8-cyclopropyl-3-propyl-6-(4-pyridylmethylamino)-3H-purine;6-cyclopentylamino-8-cylopropyl-3-propyl-3H-purine;6-butylamino-8-cyclopropyl-3-propyl-3H-purine;8-cyclopropyl-6-(2-hydroxyethylamino)-3-propyl-3H-purine;6-(3-cyclopentyloxy-4-methoxybenzylamino)-8-cyclopropyl-3-propyl-3H-purine;6-amino-8-cyclopropyl-3-propyl-3H-purine;3-ethyl-6-cyclopentylamino-8-isopropyl-3H-purine;6-cyclohexylamino-8-isopropyl-3-propyl-3H-purine;6-cyclopentylamino-8-isopropyl-3-propyl-3H-purine;3-ethyl-6-cyclopentylamino-8-cyclopropyl-3H-purine;3-(4-chlorobenzyl)-6-cyclopentylamino-8-cyclopropyl-3H-purine;6-cyclopentylamino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine;3-(2-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H-purine;8-cyclopropyl-6-diethylamino-3-propyl-3H-purine hydrochloride;8-cyclopropyl-6-(3-pentylamino)-3-propyl-3H-purine hydrochloride;6-ethylamino-8-isopropyl-3-(4-pyridylmethyl)-3H-purine;3-ethyl-8-isopropyl-6-ethylamino-3H-purine;3-ethyl-8-cyclopentyl-6-benzylamino-3H-purine;3-ethyl-8-cyclopentyl-6-ethylamino-3H-purine;3-cylcohexylmethyl-6-ethylamino-3H-purine;3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-purine;8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine;8-cyclopropyl-3-ethyl-6-propylamino-3H-purine;8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine;3-hexyl-6-methylamino-3H-purine;3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine;3-ethyl-8-isopropyl-6-benzylamino-3H-purine;3-butyl-6-ethylamino-3H-purine;3-butyl-8-cyclopropyl-6-ethylamino-3H-purine;8-cyclopropyl-6-ethylamino-3-propyl-3H-purine;8-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine;and3-ethyl-6-ethylamino-8-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine.

Other preferred adenine compounds according to the invention include:3,8-diethyl-6-morpholino-3H-purine;3-ethyl-6-ethylamino-8-((3-cyclopentyloxy-4-hydroxy)benzyl)-3H-purine;3-[3-(3-trimethylsilylethoxymethoxy)cyclopentyloxy-4-methoxy)benzyl)-6-ethylamino-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(furan-2-yl-methoxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(3-hydroxycyclopentyloxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine;6- Amino3-[3-(3-hydroxycyclopentyloxy)-4-methoxy-benzyl]-8-isopropyl-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine;6-Ethylamino-3-(3-butoxy-4-methoxy-benzyl)-8-isopropyl-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine;6-ethylamino-2-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-dimethylamino-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(3-hydroxycyclopentyloxy)-4-methoxybenzyl)]-8-(1-hydroxy-1-methylethyl)-3H-purine;6-ethylamino-9-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-isopropyl-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-amino-8-isopropyl-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(3-cyclopentyloxy-4-methoxybenzylamino)-8-isopropyl-3H-purine;6-ethylamino-8-isopropyl-3-(4-methoxybenzyl)-3H-purine;3-(3-((3-hydroxy)cyclopentyloxy)-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(N-benzoyl-N-ethylamino)-8-isopropyl-3H-purine;3-(4-chlorobenzyl)-6-cyclopropylamino-8-isopropyl-3H-purine;6-ethylamino-8-isopropyl-3-[(4-methoxy-3-(4-hydroxybutoxy))benzyl]-3H-purine;6-ethylamino-3-(4-fluorobenzyl)-8-isopropyl-3H-purine;3-(3-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine3-[3-(3-Hydroxy-cyclopentyloxy)-4-methoxy-benzyl]-8-(1-hydroxy-1-methyl-ethyl)-3H-purine;3-[3-(3-hydroxy)cyclopentyloxy)]-4-methoxy)benzyl)-6-ethylamino-8-isopropyl-3H-purine;6-amino-3-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine;6-Ethylamino-3-[3-cyclopentylmethoxy-4-methoxy-benzyl]-8-isopropyl-3H-purine;6-ethylamino-3-(3-hydroxy-4-methoxybenzyl)-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(2,2-dimethylaminoethoxy-4-methoxy)]-8-isopropyl-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-methyl-1-hydroxy)ethyl]-6-ethylamino-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-((2,2,2-trifluoroethyl)amino)-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(2,2,2)-azabicyclooctan-3-yloxy)-4-methoxy]-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(1-methylpiperidin-4-yl-methoxy)-4-methoxy-benzy]-8-isopropyl-3H-purine;6-amino-8-isopropyl-3-[(4-methoxy-3-([(4-hydroxybutoxy))benzyl]-3H-purine;3-{2-(4-chlorophenyl)-ethyl]-6-ethylamino-8-isopropyl-3H-purine;3-(4-chlorobenzyl)-6-((1-hydroxy)cyclopentylamino)-8-isopropyl-3H-purine;3-(4-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H-purine;6-amino-3(3,4-methylenedioxybenzyl)-8-isopropyl-3H-purine;6-Ethylamino-3-[(exo-8-methyl-8-azabicyclo(3,2,1)-octan-3-yl-oxy)-4-methoxy-benzy]-8-isopropyl-3-H-purine;3-(4-chlorophenyl)-6-ethylamino-8-isopropyl-3H-purine;6-ethylamino-3-[(3-hydroxy-4-methoxy)benzyl]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine;6-Ethylamino-3-[(3-pyridin-4-yl-methoxy)N-oxide-4-methoxy]-8-isopropyl-3H-purine;3-[3-Cyclohexanyl-4-oxy-4-methoxy-benzyl]-6-ethylamino-8-isopropyl-3H-purine;3-(4-chlorobenzyl)-2,6-di(ethylamino)-8-isopropyl-3H-purine;6-amino-3-(3-hydroxy-4-methoxy)-benzyl)-8-isopropyl-3H-purine;6-amino-3-[3-(4-hydroxybutoxy-4-methoxy)benzyl]-8-(1-hydroxy-1-methylethyl)-3H-purine;6-amino-3-(4-chlorobenzyl)-8-isopropyl-3H-purine;6-amino-3-cyclopentylmethyl-8-isopropyl-3H-purine;8-cyclopropyl-3-ethyl-6-ethylamino-3H-purine;6-Ethylamino-8-isopropyl-3-[3-(pyridin-4-yl-methoxy)-4-methoxy-benzyl]-3H-purine;6-Ethylamino-3-(1-oxopyridin-4-yl-methyl)-8-isopropyl-3H-purine, and6-amino-3-[(3-hydroxy-4-methoxy)benzyl)]]-8-[(1-hydroxy-1-methyl)ethyl]-3H-purine,3-(3-COOmethyl-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine,3-(3-piperadine-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine;3-(3-COOH-4-methoxbenzyl)-6-ethylamino-8-isopropyl-3H-purine,3-(3-pyrrole-benzyl)-6-ethylamino-8-isopropyl-3H-purine,3-butyl-6-pentylamino-8-cyclopropyl-3H-purine,3-butyl-6-cyclopentylamino-8-cyclopropyl-3H-purine,3-butyl-6-dimethylamino-8-cyclopropyl-3H-purine and theirpharmaceuticaly acceptable salts.

In other preferred embodiments, the adenine compound is selected fromthe group consisting of6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-methoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-methoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3,4-dimethoxy)benzyl]-8-[(1-(4-methyl)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(4-chloro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-(3-fluoro)benzyloxyamino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,5-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3,4-methylenedioxybenzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(2-thienylmethoxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3-thienylmethoxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(1-oxo-octyl)amino-1-methyl)ethyl]-3H-purine;6-amino-3-(3,4-methylenedioxybenzyl)-8-[(1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[1-(4-pyridylmethoxy)-methyl-ethyl]-3H-purine;6-ethylamino-3-(3-benzyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine;3-[(3-benzyloxy-4-methoxy)benzyl-8-[(1-benyloxy-1-methyl)-ethyl]-6-ethylamino-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-[1-(4-methoxybenzyloxy)-1-methyl-ethyl]-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-methylethenyl)-3H-purine;6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine;6-amino-8-[(1-benzyloxy-1-methyl)ethyl]-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine;[8-(1-benzyloxy-1-methyl)ethyl]3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-3H-purine;6-ethylamino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine;6-ethylamino-3-(3-,4-methylenedioxybenzyl)-8-isopropyl-3H-purine;3-(3-benzyloxy-4-methoxy-benzyl)-6-ethylamino-8-isopropyl-3H-purine;6-Amino-3-(3,4-dimethoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methylethyl]-3H-purine;6-(amino-8-(1-benzyloxy-1-methylethyl)-3-(3,4-dimethoxybenzyl)-3H-purine;6-amino-3-[(3-benzyloxy-4-methoxy)benzyl]-8-[(1-benzyloxy-1-methyl)ethyl]-3H-purine;6-Amino-3-(3,4-dimethyoxybenzyl)-8-(1-methylethenyl)-3H-purine6-amino-3-((3-benzyloxy-4-methoxy)-bezyl)-8-isopropyl-3H-purine;3-(3-benzyloxy-4-nitro-benzyl)-6-ethylamino-8-isopropyl-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-(1-methyl-ethenyl)-3H-purineand pharmaceutically acceptable salts thereof.

In certain preferred embodiments, the adenine compound is selected from3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-3H-purine (PDE IVI₅₀=2.15 μM); 3-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine (PDEIV I₅₀=1.13 μM);3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine(PDE IV I₅₀=0.32 μM); and (particularly preferred)6-cyclopentyl-8-cyclopropyl-3-propyl-3H-purine (PDE IV I₅₀=0.03 μM); andtheir pharmaceutically acceptable salts.

The present invention is also related to isoguanine compounds which areprecursors of the adenine compounds described above. In addition totheir role as precursor compounds, it has been surprisingly discoveredthat these compounds also have significant PDE IV inhibitory activity.

The present invention therefore is directed in part to a compound of theformula (II)

wherein

R₂ is O or S; and R₃, R_(6a), R_(6b) and R₈ are the same or differentand are represent the same groups as those set forth with respect tocompound (I) above.

Preferred isoguanine compounds according to the present inventioninclude6-cyclopentyamino-8-cyclopropyl-3,7-dihydro-3-propyl-2-thio-2H-purin-2-one(PDE IV I₅₀=7.41 μM);8-cyclopropyl-3,7-dihydro-6-(2-hydroxythylamino)-2-thio-2H-purin-2-one(PDE IV I₅₀=4.48 μM); (particularly preferred)8-cyclopropyl-3,7-dihydro-6-(4-pyridylmethylamino)-2-thio-2H-purin-2-one(PDE IV I₅₀=0.41 μM); and their pharmaceutically acceptable salts.

The present invention is also related to 2,6-dithioxanthine compoundswhich are precursors of the adenine compounds described above. Inaddition to their role as precursor compounds, it has been surprisinglydiscovered that these compounds also have significant PDE IV inhibitoryactivity.

The present invention therefore is directed in part to a compound of theformula (III)

wherein

R₃ and R₈ are the same or different and are represent the same groups asthose set forth with respect to compound (I) above.

Preferred dithioxanthine compounds according to the present inventioninclude3-benzyl-3,7-dihydro-8-(1-methylethyl)-2,6-dithio-1H-purin-2,6-dione(PDE IV I₁₅₀=3.40 μM); 3.03 μM);3-(4-chlorobenzyl)-8-isopropyl-3,7-dihydro-2,6-dithio-3,7-purin-2,6-dione(PDE dione (PDE IV I₅₀=2.27 μM);3-(3-cyclopentyloxy-4-methoxybenzyl)-3,7-dihydro-8-isopropyl-2,6-dithio-1H-purin-2,6-dione(PDE IV I₅₀=0.80 μM); (particularly preferred)8-cyclopropyl-3,7-dihydro-1,3-diethyl-2,6-dithio-1H-purin-2,6-dione (PDEIV I₅₀=0.42 μM); and their pharmaceutically acceptable salts.

As used herein, the following terms are intended to have the meaning asunderstood by persons of ordinary skill in the art, and are specificallyintended to include the meanings set forth below:

As used herein, the term “alkyl” means a linear or branched saturatedaliphatic hydrocarbon group having a single radical and 1-10 carbonatoms. Examples of alkyl groups include methyl, propyl, isopropyl,butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branchedalkyl means that one or more alkyl groups such as methyl, ethyl orpropyl, replace one or both hydrogens in a —CH₂— group of a linear alkylchain.

The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicylic cycloalkyl rings include adamantyland norbornyl.

The term “alkenyl” means a linear or branched aliphatic hydrocarbongroup containing a carbon—carbon double bond having a single radical and2-10 carbon atoms. A “branched” alkenyl means that one or more alkylgroups such as methyl, ethyl or propyl replace one or both hydrogens ina —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenyl groups includeethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl,2-propenyl, heptenyl, octenyl and decenyl.

The term “cycloalkenyl” means a non-aromatic monocyclic or multicyclichydrocarbon ring system containing a carbon—carbon double bond having asingle radical and 3 to 12 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl. An exemplary multicyclic cycloalkenyl ring isnorbornenyl.

The term “cycloaklylalkyl” or “cycloalkyl-alkyl” means a non-aromaticmono- or multicyclic ring system, wherein the ring is substituted withan alkyl group, as defined above to include a linear or branchedaliphatic hydrocarbon group having a single radical

The term “aryl” means a carbocyclic aromatic ring system containing one,two or three rings which may be attached together in a pendent manner orfused, and containing a single radical. Exemplary aryl groups includephenyl and naphthyl.

The term “aralkyl” or “arylalkyl” or “aryl-alkyl” means an alkyl groupas defined above to include a linear or branched saturated aliphatichydrocarbon group having a single radical, wherein the alkyl issubstituted with an aryl group, as defined above to include acarbocyclic aromatic ring system containing one, two or three ringswhich may be attached together in a pendent manner or fused, andcontaining a single radical.

The term “heterocyclic” or “heterocyclyl” means cyclic compounds havingone or more heteroatoms (atoms other than carbon) in the ring, andhaving a single radical. The ring may be saturated, partially saturatedand unsaturated, and the heteroatoms may be selected from the groupconsisting of nitrogen, sulfur and oxygen. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocyclicgroups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl; saturated 3- to 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as morpholinyl; saturated 3- to 6-memberedheteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, such as thiazolidinyl. Examples of partially saturatedheterocyclic radicals include dihydrothiophene, dihydropyran, anddihydrofuran.

The term “heteroaryl” means unsaturated heterocyclic radicals, whereinheterocyclic is as previously described. Exemplary heteroaryl groupsinclude unsaturated 3 to 6 membered heteromonocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, andpyrazinyl, unsaturated condensed heterocyclic groups containing 1 to 5nitrogen atoms, such as indolyl, quinolyl, isoquinolyl; unsaturated 3 to6 membered heteromonocyclic groups containing an oxygen atom, such asfuryl; unsaturated 3 to 6 membered heteromonocyclic groups containing asulfur atom, such as thienyl; unsaturated 3 to 6 memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; unsaturated condensed heterocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term“heteroaryl” also includes unsaturated heterocyclic radicals, whereinheterocyclic is as previously described, in which the heterocyclic groupis fused with an aryl group, in which aryl is as previously described.Exemplary fused radicals include benzofuran, benzdioxole andbenzothiophene.

The term “heterocyclylalkyl” means heterocyclic groups, as defined aboveto include compounds having one or more heteroatoms (atoms other thancarbon) in the ring, and having a single radical, wherein the ring maybe saturated, partially saturated and unsaturated, and the heteroatomsmay be selected from the group consisting of nitrogen, sulfur andoxygen, in which the heterocyclic group is substituted with an alkylgroup, as defined above to include linear or branched saturatedaliphatic hydrocarbon group having a single radical. Exemplaryheterocyclylalkyl groups include pyrrolidinyl-methyl,imidazolidinyl-methyl, piperidino-methyl, piperazinyl-methyl,morpholinyl-methyl, and thiazolidinyl-methyl.

The term “heteroaralkyl” or “heteroarylalkyl” means heteroaryl radicals,wherein heteroaryl is as previously described, wherein the heteroarylgroup is substituted with an alkyl group as defined above to includelinear or branched saturated aliphatic hydrocarbon groups having asingle radical. Exemplary heteroaralkyl groups include pyrrolyl-methyl,pyridyl-methyl, pyrimidyl-methyl, pyrazinyl-methyl, indolyl-methyl,quinolyl-methyl, isoquinolyl-methyl, furyl-methyl, thienyl-methyl,oxazolyl-methyl, benzoxazolyl-methyl, thiazolyl-methyl,benzothiazolyl-methyl, benzofuran-methyl and benzothiophene-methyl.

The term “acyl” means an H—C(O)- or alkyl-C(O)-group in which the alkylgroup is as previously described. Exemplary acyl groups include formyl,acetyl, propanoyl, and 2-methylpropanoyl.

The term “alkoxy” means an alkyl-O-group in which the alkyl group is aspreviously defined, to include a linear or branched saturated aliphatichydrocarbon group having a single radical. Exemplary alkoxy groupsinclude methoxy, ethoxy, n-propoxy, i-propoxy, and n-butoxy. The term“cycloalkoxy” means a cycloalkyl-O-group in which the cycloalkyl groupis as previously defined, to include non-aromatic mono- or multicyclichydrocarbon ring systems having a single radical. Exemplary cycloalkoxygroups include cyclopentyloxy.

The term “amido” or “aminocarbonyl” means —C(O)NH₂.

The term “amino” means the group —NH₂—. The term “alkylamino” means anamino group which has been substituted with an alkyl group as definedabove, and the term dialkylamino means an amino group which has beensubstituted with two alkyl groups, as defined above. The term“acylamino” means an amino group which has been substituted with an acylgroup as defined above.

The term “carbamyl” is the group CH₂NO.

The term “sulfonyl” means the divalent radical SO₂. The term“alkylsulfonylamino” means a sulfonyl group which is substituted with anamino group as defined above, and an alkyl group as defined above.

As used herein, the term “patient” includes both human and othermammals.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, secium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

The invention disclosed herein is also meant to encompass all prodrugsof the disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention can be administered to anyonerequiring PDE IV inhibition. Administration may be orally, topically, bysuppository, inhalation or insufflation, or parenterally.

The present invention also encompasses all pharmaceutically acceptablesalts of the foregoing compounds. One skilled in the art will recognizethat acid addition salts of the presently claimed compounds may beprepared by reaction of the compounds with the appropriate acid via avariety of known methods.

Various oral dosage forms can be used, including such solid forms astablets, gelcaps, capsules, caplets, granules, lozenges and bulk powdersand liquid forms such as emulsions, solution and suspensions. Thecompounds of the present invention can be administered alone or can becombined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

When the compounds of the present invention are incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms, are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inPharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,editors) 2nd edition, published by Marcel Dekker, Inc., incorporated byreference herein. Techniques and compositions for making tablets(compressed and molded), capsules (hard and soft gelatin) and pills arealso described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553-1593 (1980), incorporated herein by reference. Techniquesand composition for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, editors) published by Marcel Dekker, Inc., incorporated hereinby reference.

When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

The dose of the compounds of the present invention is dependent upon theaffliction to be treated, the severity of the symptoms, the route ofadministration, the frequency of the dosage interval, the presence ofany deleterious side-effects, and the particular compound utilized,among other things.

The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1 3,8-Diethyl-6-morpholino-3H-purine

(i) 38-Diethyl-hypoxanthine 3,8-diethyl-2-thioxanthine (18.9 g) wasdissolved in 370 ml of 2N NaOH Nickel aluminum alloy (75.6 g) (1.4M ofAl and 0.6M of Ni) was added in portions over 1.5 hrs at 65° C. After afurther 0.5 hr at 65-70° C. the reaction product was filtered, washedwith 200 ml of 1N NaOH and the filtrate neutralized with 183 ml of 5NHCl to pH 7. The formed aluminum hydroxide was filtered off, thefiltrate concentrated to dryness, the residue suspended in 500 ml ofabsolute ethanol at 90° C., and the insoluble NaCl filtered off andwashed. The filtrate was concentrated to dryness, dissolved in 200 ml ofchloroform, filtered and concentrated to dryness again. The residue wascrystallized from 150 ml of ethanol to give 3,8-di-ethyl-hypoxanthine(12.68 g) with mp (sublimation at 220° C.) 305-307° C. underdecomposition.

(ii) 3,8-Diethyl-6-thiohypoxanthine

The product of stage (i) (8.65 g) and phosphorus pentasulfide (12.0 g)was refluxed in 150 ml of pyridine for 1 hr. Under cooling 59.4 ml of 2NNaOH was added dropwise, the solid filtered off and washed with water.The filtrate was concentrated in vacuo to dryness and the residuesuspended in 200 ml of water and collected. The filtrate was extractedthree times with 600 ml of chloroform. The residue of the organic phasewas combined with the solid collected (total 6.08 g), dissolved in 500ml of chloroform and filtered through 24 g of silicagel. Fractions 2 and3 eluted 4.63 g of crude product which was crystallized from 120 ml ofmethanol to give 3,8-diethyl-6-thiohypoxanthine (3.58 g) with mp(sublimation at 210° C.) 250-270° C. under decomposition. A second cropgave 0.58 g.

Elemental analysis: % calc C 51.90 H 5.81 N 26.90 S 15.40 % found C51.76 H 6.01 N 26.82 S 15.64

(iii) 3,8-Diethyl-6-morpholino-3H-purine

The product of stage (ii) (52 mg) in 5 ml of morpholine was refluxed for21 hrs. Evaporation in vacuo gave 65 mg of crude3,8-diethyl-6-morpholino-3H-purine.

EXAMPLE 2 3,8-Diethyl-6-morpholino-3H-purine

(i) 3,8-Diethyl-2,6-dithioxanthine

19.14 g of 3,8-diethyl-2-thioxanthine and 22.75 g of phosphoruspentasulfide were refluxed in 280 ml of pyridine for 4.5 hrs. Aftercooling to room temperature 113 ml of 2N NaOH were added during 15minutes under vigorous stirring and cooling. The suspension wasfiltered, washed with pyridine and concentrated in vacuo. The residuewas suspended in 150 ml of water and concentrated to remove thepyridine. Suspension in water and collection of the solid gave the crudeproduct, which is dissolved in 150 ml of 1N NaOH, treated with twoportions of 0.5 g of charcoal, and filtered. The filtrate was slowlyacidified with 38 ml of 5N HCl to pH 3 and a solid collected. The driedcrude product (19.85 g) was suspended in 400 ml of 2-propanol at 95° C.After cooling to room temperature the solid (17.62 g) is collected andwashed.

(ii) 3,8-Diethyl-3,7-dihydro-6-morpholino-2H-purine-2-thione

The product of stage (i) (14.42 g) was refluxed in 78.4 ml (900 mmoles)of morpholine for 30 hours. After cooling to room temperature thereaction product was suspended in 100 ml of acetone and the titleproduct (16.49 g) collected and washed.

3,8-diethyl-3,7-dihydro-6-morpholino-2H-purine-2-thione melting point:295-298° C. (with decomposition).

Elemental analysis: Calc. C 53.22 H 6.53 N 23.87 S 10.93 Found C 53.01 H6.77 N 23.82 S 10.97

(iii) 3,8-Diethyl-6-morpholino-3H-purine

The product of stage (ii) (7.34 g) was dissolved in 150 ml of 2N NaOH.Ni—Al alloy 50% (22.95 g)(425 mmoles of Al and 196 mmoles of Ni) wasadded over 1.25 hours at 65° C. After another 1.5 hours at 65-70° C.additional 15 ml of 10N NaOH and in portions 11.48 of Ni—Al alloy 50%was added. After another 0.5 hour at 65-70° C. the reaction product wasleft over night. Dichloromethane (100 ml) was added, the suspension wasfiltered and the nickel washed with dichloromethane (200 ml) and water(100 ml). The organic phase was separated, washed twice with water andconcentrated. The residue was triturated in 50 ml of petroleum-ether togive the title product as a solid (5.40 g) mp 103-107° C.

Elemental analysis: % calc C 59.75 H 7.33 N 26.80 % found C 59.64 H 7.55N 26.35

HCl salt crystallized from acetone has mp; (sublimation 145° C.)220-222° C.

EXAMPLE 3 8-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine

(i) 8-Cyclopropyl-3-ethyl-6-ethylamino-3,7-dihydro-2H-purine-2-thione

8-cyclopropyl-3-ethyl-2,6-dithioxanthine (20.19 g) prepared according tothe method of example 2(i), and 70% ethylamine in water (320 ml 4.0M)were placed in a 450 ml pressure reactor and heated to 150° C. for 6hours. The reaction solution was cooled to room temperature, treatedwith 2 portions of charcoal (0.2 g) filtered, and evaporated to dryness.The residue was triturated in methanol (300 ml), concentrated to about200 ml, and the solid collected (16.48 g), mp 265° with decomposition.

(ii) 8-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine

The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and10N NaOH (27 ml) and heated to 65° C. Within 1.25 hours 50% Ni—Al alloy(518 mmoles of Ni and 1125 mmoles of Al) (60.8 g) was added undervigorous stirring at 65-70° C. After a further 0.75 hr at the sametemperature the reaction mixture was cooled to room temperature andtreated with chloroform (400 ml). The nickel was filtered off and washedwith 350 ml of chloroform and 150 ml of water. The filtrate wasseparated and the chloroform layer evaporated to dryness. The residue(19.64 g) was dissolved in acetone (100 ml), treated with 2 portions ofcharcoal (0.15 g) filtered, and evaporated. The residue was treated withdiethylether (100 ml) and crystals collected (6.10 g), mp 80-96° C. Asecond crop gave 1.25 g. A recrystallized sample from diisopropyletherhad mp 103-105° C.

Elemental analysis with 3.3% of water: % calc C 60.25 H 7.54 N 29.28 O2.93 % found C 60.52 H 7.46 N 29.10  O 2.92* *(by difference)

EXAMPLE 4 A.8-(3-Cyclopentyloxy-4-methoxybenzyl)-3-ethyl-6-ethylamino-3H-purineHydrochloride B.8-(3-Cyclopentyloxy-4-hydroxybenzyl)-3-ethyl-6-ethylamino-3H-purine

(i) 3-Cyclopentyloxy-4-methoxy-benzyl Alcohol

To a solution of 48.70 g (220 mmoles) of3-cyclopentyloxy-4-methoxybenzaldehyde in 250 ml of methanol was addedportionwise 8.57 g (220 mmoles) of 97% sodium borohydride within 10 minat 15-22° C. under cooling. After a further 20 min the methanol wasremoved in vacuo and the residue taken up in 10 ml of water and 300 mlof ether. The ether phase was evaporated to dryness: 48.5 g (99.2%) ofliquid benzyl alcohol.

(ii) 3-Cyclopentyloxy-4-methoxy-benzyl Cyanide

To a solution of 40.00 g (180 mmoles) of benzyl alcohol in 530 ml ofdichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionylchloride. The solution was evaporated in vacuo to dryness, which wasrepeated after toluene addition: 46.30 g (106.9%) of crude benzylchloride, which was dissolved in 230 ml of dimethylformamide and treatedwith 23.50 g (360 mmoles) of potassium cyanide. The mixture was heatedfor 4 hours to 50-55° C. The salt was filtered off and the filtrateevaporated in vacuo to dryness, which was repeated after the addition ofwater, the residue was taken up in ether and extracted with 1N NaOH. Theether phase is evaporated to dryness to yield 41.20 g (99.0%) of crudebenzyl cyanide.

(iii) (3-Cyclopentyloxy-4-methoxy-phenyl)acetyl Chloride

42.02 g (180 mmoles) of benzyl cyanide were refluxed in 410 ml of 94%ethanol, 106 ml of water, and 180 ml of 10N NaOH for 20 hours. Theethanol was removed in vacuo, the solution diluted to 800 ml with water,treated twice with 2 g of charcoal, filtered, and acidified with 185 mlof 10N HCl. The acid crystallized slowly, was collected and dried at 30°C.: 42.2 g (92.9%) of acid. 1.51 g (2.3%) could be extracted by etherfrom the filtrate. Both parts (173 mmoles) are combined and refluxed in500 ml of dichloromethane and 31.4 ml (433 mmoles) of thionyl chloridefor 1.5 hours. The solution was treated twice with 2 g of charcoal,filtered and evaporated to dryness. This was repeated twice with littletoluene: 48.70 g (>100%) of crude acetyl chloride as a reddish liquid.

(iv) 8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3-ethyl-2-thioxanthine

10.02 g (45 mmoles) of 5,6-diamino-1-ethyl-2-thiouracil hydrochloridewas dissolved in 200 ml of pyridine, treated with 6.05 g (57 mmoles) ofsodium carbonate and 15.5 g (56 mmoles) of Example 4 (iii) dissolved in25 ml of ether added within 10 minutes at 5-10° C. After 1.5 hours atroom temperature the solid was filtered off and the filtrate evaporatedin vacuo to dryness. The residue was dissolved in 100 ml of 2N NaOH and200 ml of water and brought to reflux, within 1 hour 70 ml are distilledoff. The solution was filtered and neutralized to pH 7.5 with 52 ml of5N HCl. The solid was collected and dried: 14.37 g (79.7%) of crude2-thioxanthine (from the water 4.2 g of the phenyl acetic acid wasrecovered), which was suspended in 250 ml of hot methanol and collectedagain: 10.68 g (59.3%) of purified 2-thioxanthine, which was dissolvedis 100 ml of 1N NaOH and filtered. The filtrate was acidified to pH 6and the solid collected: 8.82 g (48.9%) of 2-thioxanthine with mp (260°C.) 280-310° C. under decomposition.

(v) 8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3-ethyl-2,6-dithioxanthine

8.41 g (21 mmoles) of 2-thioxanthine are refluxed with 5.60 g (25.2mmoles) of phosphorus pentasulfide in 80 ml of pyridine. After 5.5 hours27.7 ml (55.4 mmoles) of 2N NaOH were added at 5-10° C. The solid wasfiltered off and washed with pyridine. The filtrate was evaporated invacuo to dryness, the residue is suspended in 200 ml of water withlittle tetrahydrofuran (THF) for crystallization, the suspension isconcentrated and the solid at pH 8 collected and washed. Redissolutionin 100 ml of 0.5 N NaOH, treatment with charcoal (20%), filtration andacidification to pH 6 yielded the solid crude dithioxanthine 7.84 g(89.6%). Crystallization from chloroform and suspension in hot methanolgave 5.31 g (60.7%) of dithioxanthine with mp 241-3° C. The motherliquors were combined (2.36 g) and filtered with chloroform through 60 gof silicagel in a column: 1.73 g (19.8%) were isolated as a second crop.

(vi)8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3-ethyl-6-ethylamino-37-dihydro-2H-purine-2-thione

6.67 g (16 mmoles) of dithioxanthine and 52 ml of 70% ethylamine inwater were heated to 150° C. in a pressure reactor (250 psi) for 12hours under nitrogen. The solution was treated with charcoal (5%),filtered, and evaporated in vacuo to dryness. The residue was suspendedin water, acidified with 1N HCl to pH 4 and neutralized to pH 8 withsodium bicarbonate. The solid was collected, washed and dried to give6.66 g (97.4%) of crude thioisoguanine.

(vii)

A. 8-(3-Cyclopentyloxy-4-methoxy-benzyl)-3-ethyl-6-ethylamino-3H-purineHydrochloride and B.8-(3-Cyclopentyloxy-4-hydroxy-benzyl)-3-ethyl-6-ethylamino-3H-purineHydrochloride

6.41 g (15 mmoles) of crude thioisoguanine and 9.70 g (165 mmoles) ofneutral Raney-nickel were refluxed in 70 ml of 1-propanol for 3 hours.The nickel was filtered off and the filtrate evaporated in vacuo todryness. The residue (5.86 g/98.8%) was dissolved in chloroform andextracted extensively with 1N NaOH. The NaOH solution was acidified with5N HCl to pH 4 and neutralized with sodium bicarbonate to pH 7.5. An oilprecipitated, which crystallized slowly and the solid collected: 0.49 gof 8-(3-cyclopentyloxy-4-hydroxy-benzyl)-3-ethyl-6-ethylamino-3H-purinewith mp 172-4° C. The chloroform solution was evaporated to dryness:3.76 g (63.4%) of crude 3H-purine, which was dissolved in 30 ml ofmethanol and treated with 10 ml of 1N methanolic HCl. The solution wasevaporated in vacuo to dryness and the residue crystallized fromacetone-ethyl acetate: 3.66 g (56.5%) of8-(cyclopentyloxy-4-methoxybenzyl)-3-ethyl-6-ethylamino-3H-purinehydrochloride with mp 169-71° C.

Elemental analysis for C₂₂H₃₀ClN₅O₂ Calc. C 61.17 H 7.00 N 16.21 Found C61.09 H 6.77 N 16.18

EXAMPLE 53-(3-Cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purineHydrochloride

(i) 3-Cyclopentyloxy-4-methoxy-benzaldehyde

77.70 g (500 mmoles) of isovanillin and 69.40 g (600 mmoles) of 97%potassium t-butoxide (t-BuOK) dissolved in 800 ml of 1-propanol, 69.0 ml630 mmoles), and the solution refluxed. After 3 hours another 9.25 g (80mmoles) of t-BuOK were added at 80° C. and the suspension refluxed foranother 3 hours. The solid was filtered off and the filtrate evaporatedin vacuo to dryness. The residue was dissolved in ether and extractedwith 1N NaOH. The ether phase was evaporated to dryness: 85.40 g (77.5%)of cyclopentyloxybenzaldehyde was isolated.

(ii) 3-Cyclopentyloxy-4-methoxy-benzaldehyde-oxime

85.4 g (388 mmoles) of 3-cyclopentyloxy-4-methoxy-benzaldehyde weredissolved in 350 ml of 94% ethanol and added within 10 minutes at 15-20°C. to a solution of 29.7 g (427 mmoles) of hydroxylammonium chloride and52.8 g (388 mmoles) of sodium acetate trihydrate (3 H₂O) in 230 ml ofwater. After 2 hours the ethanol was removed in vacuo, the residuetreated with 16.3 g (194 mmoles) of sodium bicarbonate until CO₂formation ceased and extracted with ether. Evaporation of the etherphase gave 91.0 g (99.7%) of oxime as a mixture of the 2 isomers.

(iii) 3-Cyclopentyloxy-4-methoxy-benzylamine

73.5 g (320 mmoles) of oxime, 80 ml of methanol, 55 g of liquid ammonia,and 18.5 g of neutral Raney-nickel are placed into a 450 ml pressurereactor. Hydrogen gas was added up to a pressure of 1,200 psi and thewhole heated to 75-80° C., when the pressure dropped to 600 psi hydrogengas was added again to 1,200 psi. After 4 hours the pressure reached1080 psi and remained constant. The nickel was filtered off and washedwith methanol. The filtrate is evaporated to dryness, dissolved in etherand extracted with 1N NaOH. The ether phase was evaporated to dryness:68.9 g (97.3%) of benzylamine.

(iv) 3-Cyclopentyloxy-4-methoxy-benzyl-isothiocyanate

82.3 g (372 mmoles) of benzylamine were dissolved in 10 ml of tolueneand added at 15-20° C. (with cooling) within 20 minutes to an emulsionof 22.5 ml (372 mmoles) of carbon disulfide and 14.88 g (372) mmoles) ofNaOH in 52 ml of water. The reaction mixture was heated to 75-80° C. for1 hour and cooled to 40° C. Within 15 minutes, 35.4 ml (372 mmoles) ofethyl chloroformate were added at 40-45° C. The emulsion was brought toabout pH 8 with 2N NaOH and heated to 55-60° C., gas formation ceasedafter about 10 hours keeping the pH at 8 with 2N NaOH (total about 8ml). The organic layer was collected and the solvent evaporated: 96.3 g(98.3%) of benzyl isothiocyanate.

(v) 1-(3-Cyclopentyloxy-4-methoxy-benzyl)-2-thiourea

96.3 g (366 mmoles) of benzylisothiocyanate were dissolved in 100 ml oTHF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution. After0.5 hour at 40-45° C., 300 ml of water were added and the THF removed invacuo. The gummy suspension is treated with 200 ml of ether, thecrystals collected and washed with water and ether. Suspension in 30 mlof methylenechloride and collection gave 65.77 g (64.2%) ofbenzyl-2-thiourea with mp 144-5° C.

(vi) 6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thiouracil

29.65 g (256 mmoles) of 97% t-BuOK were dissolved in 240 ml of2-propanol. 65.33 g (233 mmoles) of 2-thiourea and 25.3 ml (238 mmoles)of ethyl cyanoacetate were added at 80° C. After 30 minutes at reflux asolution was formed and after 4.5 hours an additional 2.96 g (25.6mmoles) of t-BuOK and 4.97 ml (46.6 mmoles) of ethyl cyanoacetate added.After 22 hours of refluxing the solid was collected, combined with theresidue of the filtrate, dissolved in 1 l of water and precipitated withabout 50 ml of 5N HCl (pH 3-4). The solid is collected, washed, dried,recrystallized by suspension in 1 l of refluxing acetone, concentratedto about 300 ml and collected at 23° C.: 80.65 g (85.7%) of uracilcontaining 1 equivalent of acetone, mp 225-7° C.

(vii)6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-nitroso-2-thiouracil

68.9 g (170 mmoles) of uracil are dissolved in 650 ml of acetic acid,for removal of acetone 100 ml are distilled off in vacuo, and at 65-70°C. 43.4 ml (174 mmoles) of 4N sodium nitrite solution were added within10 minutes. After further 5 minutes the suspension was cooled to 30° C.and diluted with 1.7 l of water. The solid was collected, washed, anddried: 64.08 g (100%) of nitrosouracil, which was dissolved in 330 ml of1N NaOH and 300 ml of water, filtered, and acidified with 5N HCl to pH2, to keep it in suspension 2 l of water were added. The solid wascollected and washed, suspended in 60 ml of methanol and collectedagain: 54.2 g (84.7%) of nitrosouracil.

(viii) 1-(3-cyclopentyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil

15.06 g (40 mmoles) of nitrosouracil are suspended in 300 ml of THF andhydrogenated with hydrogen gas and 6 g of neutral Raney-nickel for 2.5hours, when hydrogen uptake ceased. After 1 hour all was dissolved andthereafter a new precipitate formed, which is dissolved in a mixture ofmethylenechloride and methanol. The nickel was filtered off and thefiltrate evaporated in vacuo to dryness: 13.96 g (96.3%) of crudediaminouracil.

(ix)6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-isobutyrylamino-2-thiouracil

A two phase solution of 15.01 g (41.4 mmoles) of diaminouracil, 180 mlof THF, 150 ml of water, 6.96 g (82.8 mmoles) of sodium bicarbonate, and10.52 ml (62.1 mmoles) of isobutyric anhydride is heated to 55° C. undernitrogen for 1 hour. The THF was evaporated in vacuo and the residuediluted with 200 ml of water (pH 8). The solid was collected, washed,and dried: 16.25 g (90.7%) of isobutyrylaminouracil.

(x) 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-2-thioxanthine

17.81 g (41.2 mmoles) of isobutyrylaminouracil were refluxed for 0.75hour in 120 ml of 1N NaOH and 80 ml of water. The solution was treatedtwice with 0.5 g of charcoal, filtered, acidified with 5N HCl, and putto pH 7-8 with sodium bicarbonate solution. The solid was collected,washed, and dried: 15.31 g (89.6%) of 2-thioxanthine with mp 270-6° C.(with decomposition).

(xi)3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-2,6-dithioxanthine

15.17 g (36.6 mmoles) of 2-thioxanthine and 9.76 g (43.9 mmoles) ofphosphorus pentasulfide were refluxed under nitrogen in 140 ml ofpyridine for 5.5 hours. At 5-10° C. 48.3 ml (96.6 mmoles) of 2N NaOHwere added dropwise. The solid was filtered of and washed with pyridine.The filtrate was evaporated in vacuo to dryness and treated with 300 mlof water. The suspension was adjusted to pH 7 with sodium bicarbonatesolution and the solid collected, washed, dissolved in 200 ml of 0.5NNaOH solution, treated twice with 1.6 g of charcoal, filtered, acidifiedwith 5N HCl and neutralized with sodium bicarbonate solution to pH 7.The solid was collected, washed, and dried: 14.64 g (92.9%) of crudedithioxanthine, which was dissolved in 400 ml of methylenechloride andfiltered through 60 g of silicagel in a column. The solvent wasevaporated and the residue suspended in 20 ml of 100% ethanol andcollected: 14.34 g (82.2%) of dithioxanthine with mp 204-6° C.(containing 1 mol EtOH).

(xii)3-(3-Cyclopentyloxy-4-methoxy-benzyl)-3,7-dihydro-6-ethylamino-8-isopropyl-2H-purine-2-thione

6.20 g (13 mmoles) of dithioxanthine and 42 ml of 70% ethylamine inwater were placed into a 450 ml pressure reactor and heated to 150° C.(240 psi) for 12 hours. The solution was filtered and evaporated todryness. The residue was suspended in water, acidified with 1N HCl to pH3, and neutralized with sodium bicarbonate solution to pH 7-8. The solidwas collected, washed, and dried: 5.48 g (95.5%) of thioisoguanine withmp 72-7° C.

(xiii)3-(3-Cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purineHydrochloride

5.43 g (12.3 mmoles) of thioisoguanine and 7.9 g of neural Raney-nickelwere refluxed in 60 ml of 1-propanol for 4.5 hours. The nickel wasfiltered off and the filtrate evaporated in vacuo to dryness: 4.90 g(97.2%) of crude purine, which was dissolved in 20 ml of chloroform,extracted with 1N NaOH and filtered through 30 g of silicagel in acolumn. The solvent was evaporated, the residue dissolved in 25 ml ofmethanol, treated with 11 ml of methanolic 1N HCl solution andevaporated to dryness. The residue was suspended in 80 ml of ethylacetate and collected: 3.49 g (63.6%) of 3H-purine hydrochloride with mp202-12° C.

Elemental analysis for C₂₃H₃₂ClN₅O₂ Calc. C 61.94 H 7.23 N 15.70 O 7.17Found C 62.17 H 7.02 N 15.66 O 7.30

EXAMPLE 6 3-(3-Cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-3H-purineHydrochloride

(i) 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-2-thioxanthine

14.62 g (40 mmoles) of1-(3-cyclopentyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil weredissolved in 200 ml of formic acid. The solution was concentrated invacuo at room temperature to remove the water. 50 ml of formic acid wereadded and the procedure repeated. After a total of 1 hour the formicacid solution was concentrated to 30 ml at 25° and diluted with 300 mlof water. The crystals were collected, washed, and dried: 13.48 g(86.3%) of crude 5-formamide (mp 210-30° C.), which was refluxed in 86ml of 1N NaOH for 15 min. The turbid solution was treated twice with 0.6g of charcoal, filtered, acidified with 5N HCl to pH 2, and neutralizedto pH 6.5. The amorphous solid was collected, washed, and dried at 60°C.: 11.93 g (80.1%) of crude 2-thioxanthine, which was dissolved in 150ml of THF, treated with charcoal (5%), filtered, concentrated to 40 ml,and diluted with 250 ml of ethanol. After concentration to 120 ml theformed solid is collected, washed, and dried: 9.21 g (61.9%) of2-thioxanthine with mp 254-65° C.

Elemental analysis for C₁₈H₂₀N₄O₃S Calc. C 58.05 H 5.41 N 15.04 O 12.89Found C 58.13 H 5.41 N 14.93 O 13.11

(ii) 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-2,6-dithioxanthine

8.94 g (24 mmoles) of 2-thioxanthine and 6.40 g (28.8 mmoles) ofphosphorus pentasulfide were refluxed in 96 ml of pyridine undernitrogen for 1.5 hours. At 5-10° C. 31.7 ml (63.4 mmoles) of 2N NaOHwere added under cooling and the mixture diluted with 30 ml of pyridine.The solid was filtered off and the filtrate evaporated in vacuo todryness. The residue was suspended in 30 ml of water and the solidcollected, dissolved in 160 ml of 0.5N NaOH, filtered, treated withcharcoal (20%), filtered again, acidified with 5N HCl to pH 5, the solidcollected, washed, and dried: 9.03 g (96.9%) of crude dithioxanthine.The product was dissolved in 400 ml of chloroform and filtered through30 g of silicagel in a column. The solvent was removed in vacuo, theresidue dissolved in 50 ml of THF, filtered, concentrated to 30 ml,diluted with 200 ml of ethanol, concentrated again to 150 ml and thesolid collected, washed, and dried: 8.65 g (92.8%) of dithioxanthinewith mp 215-8° C.

Elemental analysis for C₁₈H₂₀N₄O₂S₂ with 0.25M of ethanol and 0.5M ofwater Calc. C 54.32 H 5.54 N 13.70 O 10.76 Found C 54.67 H 5.32 N 13.80O 10.20

(iii)3-(3-Cyclopentyloxy-4-methoxy-benzyl)-3,7-dihydro-6-ethylamino-2H-purine-2-thione

4.66 g (12 mmoles) of dithioxanthine and 48.3 ml (60 mmoles) of 70%ethylamine in water were heated to 150° C. in a 450 ml pressure reactorunder N₂ for 12 hours (240 psi). The solution was treated with charcoal(5%), filtered and evaporated to dryness. The residue was taken up in100 ml of water, acidified with 1N HCl to pH 3 and neutralized withsodium bicarbonate to pH 7, and the solid collected: 4.43 g (92.5%) ofcrude thioisoguanine with mp 99-103° C.

(iv) 3-(Cyclopentyloxy-4-methoxy-benzyl)-6-ethylamino-3H-purineHydrochloride

4.39 g (11 mmoles) of thioisoguanine and 7.10 g (121 mmoles) of neutralRaney-nickel are refluxed in 50 ml of 1-propanol for 4.5 hours. Thenickel was filtered off and the filtrate evaporated to dryness. Theresidue (3.79 g/93.8%) was dissolved in 20 ml of chloroform and 0.4 mlmethanol and filtered through 24 g of silicagel in a column also with 2%methanol. The combined fractions were washed with 1N NaOH and theorganic phase evaporated to dryness. The residue (2.69 g/66.6%) wasdissolved in 30 ml of dichloromethane and 0.6 ml methanol and againfiltered through 30 g of silicagel. A total of 1.86 g (46.0%) of3H-purine was isolated, which was dissolved in 20 ml of methanol,treated with 5.4 ml of 1N methanolic HCl, and evaporated in vacuo todryness. Crystallization and recrystallization from dichloromethane andethyl acetate gave 1.75 g (39.4%) of 3H-purine hydrochloride with mp170-85° C.

Elemental analysis for C₂₀H₂₆C₁N₅O₂ Calc. C 59.47 H 6.49 N 17.34 O 7.92Found C 59.72 H 6.44 N 17.25 O 8.24

EXAMPLE 7 8-Cyclopropyl-6-(4-pyridylmethyl-amino)-3-propyl-3H-purineDihydrochloride

(i) 8-Cyclopropyl-3-propyl-2,6-dithioxanthine

In a 5 L 3-necked flask fitted with a mechanical stirrer and a condenserwith a drying tube were placed 2.2 L of pyridine and8-cyclopropyl-3-propyl-2-thio-xanthine (220 g, 0.88 mol). Phosphoruspentasulfide (236 g, 1.06 mol) was added and the mixture was heatedunder reflux for 5 hours and stored overnight at room temperature. Thereaction mixture was cooled to 5-10° and 3 N aqueous sodium hydroxide(770 ml) was added over 1.5 hours with stirring. Stirring was continuedfor 30 minutes after removal of the cooling bath and the precipitatedproduct was collected by suction filtration. The filter cake was washedsuccessively with pyridine (300 ml) and four 300 ml portions oftetrahydrofuran. The solvents are evaporated in vacuo and the solidresidue was stirred with water (750 ml), filtered and washed with water.The crude product was dissolved in 1.7 L of 1 N sodium hydroxide andstirred with 15 g of Darco G-60. The charcoal was filtered and thetreatment was repeated with a fresh portion of charcoal. The solutionwas acidified to pH 1.5 with 6 N hydrochloric acid and the pale yellowprecipitate was collected. The solid was dissolved again in 1.7 L of 1Nsodium hydroxide and treated successively with two portions of charcoalas above. The solution was acidified and the precipitate was collectedand washed with water. After drying to constant weight at 54° C. undervacuum, there was obtained 128 g (56%) of the title compound, mp over245° C.

(ii)8-Cyclopropyl-3,7-dihydro-3-propyl-6-(4-pyridylmethylamino)-2H-purine-2-thione

5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxanthine and21.3 ml (200 mmoles) of 95% 4-picolylamine were heated under argon to150-5° C. After 14 hours the cooled solution was poured into 100 ml ofwater, acidified with 19 ml of 10N HCl and 1N HCl to pH 6, where anorange colored gum was formed. With sodium bicarbonate the mixture wasneutralized to pH 7. With time the gum crystallized and the solid iscollected and washed. The residue was suspended in acetone and thecrystals collected: 3.92 (57.6%) of crude product. The filtrate wasevaporated to dryness, dissolved in 40 ml of 0.5N NaOH, extracted 4times with methylenechloride, and acidified again with 5N HCl to pH 6.Again the gum crystallized over 48 hours and the mixture was neutralizedto pH 7 with bicarbonate and the solid collected: 1.75 g (25.7%) ofcrude product. Both parts were dissolved in 30 ml of methylenechlorideand filtered through 30 g of silicagel in a column. 150 mg (2.8%) ofstarting material was recovered first, then 5.04 g (74.0%) of productwas recovered with 5% of methanol, which was dissolved in 32 ml of 1NHCl, treated with 250 mg of charcoal, filtered, and neutralized with 7.5ml of 2N NaOH and sodium bicarbonate solution to pH 7-8. The water phasewas decanted from the gum and the latter washed with water andcrystallized from acetone: 4.08 g (59.9%) of thioisoguanine with mp204-210° C. with decomposition.

(iii) 8-Cyclopropyl-6-(4-pyridylmethylamino)-3-propyl-3H-purineDihydrochloride

3.06 g (9 mmoles) of thioisoguanine and 5.8 g of neutral Raney-nickelwere refluxed under argon in 1-propanol for 4 hours. The nickel wasfiltered off and washed with methanol. The filtrate as evaporated todryness, the residue dissolved in 20 ml of methylenechloride, thesolution extracted with 1N NaOH, and evaporated to dryness: 2.43 g(87.4%) of crude purine, which was dissolved in 20 ml of methanol,treated with 17 ml of 1N methanolic HCl and evaporated again to dryness.Crystallization from isopropanol gives 1.09 g (36.3%) of purinedihydrochloride with mp 157-65° C.

EXAMPLE 8 6-Cyclopentylamino-8-cyclopropyl-3-propyl-3H-purineHydrochloride

(i)6-Cyclopentylamino-8-cyclopropyl-3,7-dihydro-3-propyl-2H-purine-2-thione

5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxantine and 42ml of cyclopentylamine were heated in a 450 ml pressure reactor to 150°C. (50 psi) with the exclusion of air. After 20 hours the solution wastransferred with methanol to a round bottom flask and evaporated invacuo to dryness. The residue is treated with 60 ml of water and 5N HClto obtain a pH of 2. The suspension is neutralized with bicarbonate topH 7, the solid collected, washed, dried, suspended in refluxing acetoneand collected again: 5.98 g of thioisoguanine with mp 274-6° C.(decomp).

(ii) 6-Cyclopentylamino-8-cyclopropyl-3-n-propyl-3H-purine Hydrochloride

4.49 g (14.1 mmoles) of thioisoguanine and 9.2 g of neutral Raney-nickelwere refluxed in 45 ml of 1-propanol for 5 hours. The nickel wasfiltered off and the filtrate evaporated to dryness. The residue (>100%)was dissolved in 30 ml of methanol, treated with 16.9 ml of 1Nmethanolic HCl solution, and evaporated to dryness. The residue wasdissolved in methylenechloride, treated with 0.12 g of charcoal,filtered, concentrated, diluted with acetone and the remaining methylenechloride removed by distillation. The crystals were collected: 4.18 g(92.3%) of purine hydrochloride with mp 218-221° C.

Elemental analysis for C₁₆H₂₄ClN₅ M.W. 321.86 Calc. C 59.71 H 7.52 N21.76 Cl 11.01 Found C 59.82 H 7.40 N 21.76 Cl 11.02 (diff)

EXAMPLE 96-Amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purineHydrochloride A.6-Amino-5-(2-benzyloxy-2-methyl-propionylamino)-1-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thiouracil

A solution with 26.39 g (124 mM) of 2-benzyloxy-2-methyl-propionylchloride in 86 ml of THF was added at 5-10° C. within 20 min to astirred suspension with, 31.99 g (84.4 mM) of1-(3-cyclopentyloxy-4-methoxy-benzyl)-4,5-diamino-2-thiouracil in 315 mlof THF and 26.5 ml of triethylamine. After 2 hr at rt the solid wasfiltered off and the solution evaporated to dryness. The residue wastreated with 400 ml of ether, 50 ml of saturated sodium bicarbonatesolution and 100 ml of water. After 2 hr the crystals were collected andwashed with ether and water: 30.14 g (66.3%) of amide. The ether phasewas evaporated to dryness and the residue crystallized from methanol:5.30 g (11.7%) of amide with mp 198-202° C.

B.8-(1-Benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thioxanthine

35.44 g (65.8 mM) of the above amide (A.) were added at 70° C. to asolution with 29.53 g of t-BuOK in 350 ml of isopropanol and refluxedfor 0.5 hr. The solvent was evaporated in vacuo, the residue dissolvedin 350 ml of water, the solution treated twice with 3.0 g of charcoaland filtered. At 5° C. the solution was neutralized with 56 ml of 5n HClto pH 7. After 2.5 hr the solid was collected and suspended for 1.5 hrin 300 ml of methanol, cooled to 5° C. and the solid collected again:21.15 g (61.7%) of xanthine. The filtrate was evaporated in vacuo, theresidue dissolved in dichloromethane and filtered through 60 g ofsilicagel in a column: crystallization from methanol gave another 5.75 g(16.8%) of xanthine with mp 158-160/235-237/288-290° C.

C.8-(1-Benzyloxy-1methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-hypoxanthine

A solution with 22.39 g (43 mM) of the above xanthine (B.) in 580 ml of1-propanol was treated with 25 g of Raney-nickel (washed with 0.1%aqueous acetic acid) and refluxed for 2 hr. The nickel was filtered offand the solvent evaporated in vacuo. The residue was crystallized from120 ml of methanol: 12.73 g (60.6%) of hypoxanthine with mp 161-162° C.,a second crop gave 1.97 g (9.4%) of hypoxanthine.

D.6-Amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3-H-purineHydrochloride

2.44 g (5 mM) of the above hypoxanthine (C.) and 25 ml of phosphorusoxychloride were heated at 65-70° C. for 35 min. The solution wasevaporated in vacuo and repeated twice with toluene. The residue wasdissolved in 55 ml of THF and added to 3.3 ml of 32% aqueous ammoniasolution. After the transfer to a 450 ml pressure reactor and asupplement of 50 g of liquid ammonia the mixture was heated to 60° C.(340 psi) for 3.5 hr. The solid was filtered off and the solventevaporated in vacuo. The residue was dissolved in chloroform andextracted with 1 n NaOH solution. The chloroform residue was dissolvedin 25 ml of methanol and treated with 5 ml of 1 m methanolic HClsolution. The solvents were evaporated in vacuo and the residue wassuspended in hot methanol and the solid collected at 5° C.: 2.07 g(79.0%) of adenine with mp 201-203° C., from acetone a second crop of0.28 g (10.7%) was collected.

Elemental analyses for C₂₈H₃₄ClN₅O₃/524.06;

% calc C 64.17 H 6.54 N 13.36 O 9.16 % found C 64.13 H 6.58 N 13.31 O9.15

EXAMPLE 108-(1-Benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-6-ethylamino-3H-purineHydrochloride

1.95 g (4 mM) of8-(1-benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-hypoxanthineand 20 ml of phophorus oxychloride were heated to 70° C. for 0.5 hr. Thesolution was evaporated in vacuo and repeated twice with toluene. Theresidue was dissolved in 30 ml of THF and added to 16 ml of 70% aqueousethylamine solution at 5° C. After 1 hr at rt the solvents wereevaporated in vacuo. The residue was dissolved in 50 ml ofdichloromethane and extracted with 1 n NaOH solution. The organic phasewas evaporated in vacuo, the residue dissolved in 20 ml of methanol,treated with 4.4 ml of 1 m methanolic HCl solution and evaporated again.The residue was crystallized from ethyl acetate: 1.85 g (83.7%) ofadenine with mp 148-150° C. From ethyl acetate-ether a second crop of0.17 g (7.7%) was obtained.

Elemental analyses for C₃₀H₂₈ClN₅O₃/552.12;

% calc C 65.26 H 6.94 N 12.68 O 8.69 % found C 65.07 H 6.95 N 12.53 O8.96

EXAMPLE 116-Amino-3-(3,4-methylenedioxy-benzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-3H-purineHydrochloride A.6-Amino-1-(3,4-dimethoxy-benzyl)5-(2-(4-fluorobenzyloxy-2-methyl-propionylamino)-2-thiouracil

A solution with 3.70 g (15 mM) of2-(4-fluorobenzyloxy)-2-methyl-propionyl chloride in 10 ml of THF wasadded at 0-5° C. within 5 min to a suspension with 3.19 g (10.3 mM) of5,6-diamino-1-(3,4-dimethoxybenzyl)-2-thiouracil and 3.5 ml of (25 mM)of triethylamine in 30 ml of THF. After 4 hr the solid was filtered offand the solvent evaporated in vacuo. The residue was dissolved in 40 mlof ethyl acetate and extracted with 20 ml of 1 n HCl solution. Aprecipitate was formed and collected: 2.11 g (40.6%) of amide. The ethylacetate phase was washed with sodium bicarbonate solution and evaporatedto dryness: 3.70 g of a mainly two compound mixture. Separation of adichloromethane solution, comprising 2% of methanol, on 60 g ofsilicagel in a column gave first after crystallization from acetone 1.11g (15.4%) of the diamide with mp 194-197° C. and later fractions gave1.06 g (20.4%) of amide with mp 110-180° C. as a second crop.

B.3-(3,4-Dimethoxybenzyl)-8-(1-(4-fluorobenzyloxy-1-methyl-ethyl)-2-thioxanthine

A solution with 3.07 g (6.1 mM) of the above amide (A.) in 30 ml of 1 nNaOH was refluxed for 15 min, treated twice with 0.2 of charcoal,filtered and neutralized with 6.2 ml of 5 n HCl. The solid wascollected, suspended in 30 ml of hot methanol and collected again at 5°C.: 2.34 g (79.1%) of xanthine with mp 300-302° C.

C.3-(3,4-Dimethoxybenzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-hypoxanthine

2.18 g (4.5 mM) of xanthine (B.) and 2.6 g of Raney-nickel (treated with0.1% aqueous acetic acid) were refluxed in 30 ml of 1-propanol for 2.5hr. The nickel was filtered off and the solution evaporated in vacuo todryness. The residue was dissolved in 40 ml of ethyl acetate andextracted with sodium bicarbonate solution. The formed solid is filteredoff and the organic phase evaporated in vacuo to dryness (1.95 g). Adichloromethane solution, comprising 2% of methanol, was purified on 19g of silicagel in a column. Crystallization from ethyl acetate gave 1.37g (67.2%) of hypoxanthine with mp 159-161° C., a second crop gave 0.4 g(2.0%) of hypoxanthine.

D.6-Amino-3-(3,4-dimethoxybenzyl)-8-(1-(4-fluorobenzyloxy-1-methyl-ethyl)-3H-purineHydrochloride

1.27 g (2.8 mM) of the above hypoxanthine (C.) was heated in 13 ml ofphosphorus oxychloride to 70° C. for 30 min. Evaporation in vacuo andtwice repetition with toluene gave the crude 6-chloro intermediate,which was dissolved in 40 ml of THF and added at 0-5° C. to 12 ml of 32%aqueous ammonia. After the addition of 50 g of liquid ammonia thesolution was heated to 60° C. in a 450 ml pressure reactor (340 psi).After 3.5 hr the solid was filtered off and the solution evaporated invacuo to dryness. The residue was dissolved in dichloromethane,extracted with 1 n NaOH and evaporated again to dryness. The residue wasdissolved in 20 ml of methanol, treated with 2.9 ml of 1 m methanolicHCl and evaporated to dryness. Crystallization from ethyl acetate gave1.24 g (90.5%) of title adenine with mp 172-175° C.

Elemental analyses for C₂₄H₂₇ClFN₅O₃/487.96;

% calc C 59.07 H 5.58 N 14.35 O 9.84  % found C 58.95 H 5.75 N 14.24 O10.10

EXAMPLE 126-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)8-(1-(4-methoxybenzyloxy)-1-methyl-ethyl)-3H-purineHydrochloride A.6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-(2-(4-methoxybenzyloxy)-2-methyl-propionylamino)-2-thiouracil

A solution with 2.91 g (12 mM) of crude2-(4-methoxybenzyloxy)-2-methyl-propionyl chloride in 9 ml of THF wasadded within 90 min to a stirred suspension with 3.62 g (10 mM) of5,6-diamino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thiouracil. After 20hr another 485 mg of chloride in 5 ml of THF was added within 30 min.After a further 3 hr the solid was filtered off and the solutionevaporated in vacuo to dryness. The residue was dissolved in ethylacetate, extracted with sodium bicarbonate solution and the organicphase evaporated in vacuo to dryness. The residue was crystallized frommethanol: 1.71 g (30.1%) of amide with mp 172-184° C.

B.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-methoxybenzyloxy)-1-methyl-ethyl)-2-thioxanthine

3.30 g (5.8 mM) of the above amide (A.) and 2.60 g of t-BuOK (23 mM)were refluxed in 33 ml of isopropanol for 45 min. The solvent wasremoved in vacuo, the residue dissolved in 50 ml of water, treated twicewith 0.3 g of charcoal, filtered, acidified with 4.5 ml of 5 n HCl to pH4.5and neutralized with sodium bicarbonate solution. The solid wascollected and crystallized from methanol: 2.48 g (77.7%) of xanthinewith mp 169/276-279° C.

C.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-methoxybenzaloxy)-1-methyl-ethyl)-hypoxanthine

A solution with 2.34 g (4.25 mM) of the above xanthine (B.) and 2.5 g ofRaney-nickel (treated with 0.1% of aqueous acetic acid) were refluxed in35 ml of 1-propanol. After 2.5 hr the nickel was filtered off and thesolvent evaporated in vacuo. The residue was dissolved in ethyl acetate,extracted with sodium bicarbonate solution and concentrated in vacuo toabout 10 ml. Over night crystallization gave 1.29 g (58.6%) ofhypoxanthine with mp 156-157° C.

D.6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-methoxybenzyloxy)-1-methyl-ethyl)-3H-purine-hydrochloride

1.14 g (2.2 mM) of the above hypoxanthine (C.) and 12 ml of phosphorusoxychloride were heated to 70° C. for 40 min. Evaporation in vacuo andrepetition twice with toluene gave the crude 6-chloro derivative whichwas dissolved in 40 ml of THF and added to 12 ml of 32% aqueous ammoniasolution. After supplemented with 50 g of liquid ammonia the solutionwas heated to 60° C. in a 450 ml pressure reactor (340 psi) for 3.5 hr.The solvent was evaporated in vacuo, the residue dissolved inchloroform, the solution extracted with 1 n NaOH and evaporated in vacuoto dryness. The residue was dissolved iri methanol treated with 2.3 mlof 1 m methanolic HCl and evaporated in vacuo to dryness. The residuewas crystallized from acetone and suspended in water-ether.

EXAMPLE 136-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-pyridylmethoxy)-1-methyl-ethyl)-3H-purinedihydrochloride A.6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-(2-(4pyridylmethoxy)-2-methyl-propionylamino-2-thio-uracil

3.58 g (14.3 mM) of 2-(4-pyridylmethoxy-2-methyl-propionyl chloridehydrochloride were added to a solution of 3.61 g (10 mM) of1-(3-cyclopentyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil in 82 mlof pyridine. After 48 hr the solution was heated to 50° C. for 3 hr.4.15 g (30 mM) of potassium carbonate were added and after an additional24 hr of stirring the solid was filtered off and the solution evaporatedin vacuo to dryness. The residue was suspended in 50 ml of water and 10ml of THF. The crystals were collected suspended in 50 ml of hot acetoneand concentrated. The solid was collected at 0-5° C.: 3.34 g (61.9%) ofamide with mp 245-247° C.

B.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-pyridylmethoxy)-1-methyl-ethyl)-2-thioxanthine

3.24 g (6 mM) of the above amide (A.) were refluxed for 40 min in asolution of 2.78 g (24 niM) of t-BuOK in 32 ml of isopropanol. Thesolution was evaporated in vacuo to dryness, the residue dissolved in 50ml of water, the solution treated twice with 0.3 g of charcoal, filteredand neutralized with 4.5 ml of 5 n HCl. The solid was collected,suspended in 40 ml of hot methanol, concentrated to 20 ml and collectedagain at 0-5° C.: 2.40 g (76.7%) of xanthine with mp 210-213/286-288° C.

C.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-pyridylmethoxy)-1-methyl-ethyl)-hypoxanthine

2.19 g (4.2 mM) of the above xanthine (B.) were refluxed with 2.5 g ofRaney-nickel (treated with 0.1% of aqueous acetic acid) in 30 ml of1-propanol for 2.5 hr. The nickel was filtered off and the solutionevaporated in vacuo to dryness. The residue was dissolved in in 40 ml ofdichloromethane, the solution extracted with sodium bicarbonate solutionand the organic phase evaporated in vacuo to dryness. The residue wasdissolved in a 19:1 mixture of dichloromethane and methanol, filteredthrough 30 g of silicagel in a column and evaporated again to dryness:1.48 g (71.8%) of crude hypoxanthine.

D.6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-pyridylmethoxy)-1-methyl-ethyl)-3H-purine-dihydrochloride

1.48 g (3.0 mM) of the above crude hypoxanthine (C.) and 15 ml ofphosphorus oxychloride were heated to 65-70° C. for 40 min. The solutionturned purple immediately and was evaporated in vacuo to dryness andrepeated twice with toluene. The crude chloride was dissolved in 40 mlof THF and 12 ml of 32% aqueous ammonia. After the transfer to a 450 mlpressure reactor supplemented with 50 g of liquid ammonia and heated to60° C. for 4 hr (340 psi). The mixture was evaporated in vacuo todryness. The residue was dissolved in chloroform, the solution extractedwith In NaOH solution and the organic phase evaporated in vacuo todryness. The residue was dissolved in a 19:1 mixture of dichloromethaneand methanol and chromatographed on 30 g of silicagel in a column.

EXAMPLE 146-Amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(34-dimethoxybenzyl)-3H-purineHydrochloride

In analogy to example 9 we prepared from5,6-diamino-1-(3,4-dimethoxybezyl)-2-thiouracil and2-benzyloxy-2-methyl-propionyl chloride the following compounds:

A.6-Amino-5-(2-benzyloxy-2-methyl-propionylamino)-1-(3,4-dimethoxybenzyl)-2-thiouracil

B. 8-(1-Benzyloxy-1-methyl-ethyl)-3-(3,4-dimethoxybenzyl)-2-thioxanthine

C. 8-(1-Benzyloxy-1-methyl-ethyl)-3-(3,4-dimethoxybenzyl)-hypoxanthinewith mp 164-166° C.

D.6-Amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(3,4-dimethoxybenzyl)-3H-purinehydrocloride

with mp 184/190-191° C.; Elemental analyses for C₂₄H₂₈ClN₅O₃;

% calc C 61.34 H 6.01 N 14.90 O 10.21 % found C 61.30 H 6.15 N 14.89 O10.28

EXAMPLE 156-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-3H-purinehydrochloride

In analogy to example 9 we prepared from1-(3-cyclopentyloxy-4-methoxy-benzyl)-4,5-diarmino-2-thiouracil and2-(4-fluorobenzyloxy)-2-methyl-propionyl chloride the followingcompounds:

A.6-Amino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-5-(2-(4-fluorobenzyloxy)-2-methyl-propionylamino)-2-thiouracilwith mp 185-193° C.

B.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-2-thioxanthinewith mp 188-192/288-296° C.

C.3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-hypoxanthinewith mp 131-134° C.

D.6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-(4-fluorobenzyloxy)-1-methyl-ethyl)-3H-purinehydrochloride with mp 165-174° C.

EXAMPLE 168-Benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-6-ethylamino-3H-purinehydrochloride

In analogy to example 9 we prepared from benzyloxyacetyl chloride and1-(3-cyclopentyloxy-4-methoxy-benzyl)-4,5-diamino-2-thiouracil thefollowing compounds:

A. 6-Amino-5-benzyloxyacetylamino-2-thiouracil with mp 195-196° C.

B.8-Benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thioxanthinewith mp 101-103° C.

C. 8-Benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-hypoxanthinewith mp 190-194° C.

D.8-Benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-6-ethylamino-3H-purinehydrochloride with mp 179/196-198° C.

Elemental analyses for C₂₈H₃₄ClN₅O₃/524.06;

% calc C 64.17 H 6.54 N 13.36 O 9.16 % found C 63.91 H 6.62 N 13.39 O9.14

EXAMPLE 17 Thioisoguanine Derivatives

Following the previously set forth methods, the following thioisoguaninederivatives of the present invention were synthesized. The chemical nameand melting point are provided in Table 1 below.

TABLE 1 THIOISOGUANINES Compouud m.p. (° C.)3,8-diethyl-3,7-dihydro-6-morpholino-2H-2-thio-purin-2- 295- one298(dec) 3-(cyclopropylmethyl)-3,7-dihydro-8-isopropyl-6- 208-210propylamino-2-thio-2H-purin-2-one3,7-dihydro-6-ethylamino-3-hexyl-2-thio-2H-purin-2-one 235-2373,7-Dihydro-3-hexyl-6-methylamino-2-thio-2H-purin-2- 217-219 one3-benzyl-3,7-dihydro-6-methylamino-2-thio-2H-purin-2- 253-255 one8-cyclopropyl-3,7-dihydro-6-ethylamino-3-(3- 250-254methylbutyl)-2-thio-2H-purin-2-one8-cyclopropyl-3,7-dihydro-3-ethyl-6-propylamino-2-thio- 270-2722H-purin-2-one 3-butyl-3,7-dihydro-6-ethylamino-2-thio-2H-purin-2-one(220) 246-248 3-butyl-8-cyclopropyl-3,7-dihydro-6-ethylamino-2-thio-226-228 2H-purin-2-one6-ethylamino-3,7-dihydro-3-propyl-2-thio-2H-purin-2- 247-251 one8-cyclopropyl-6-ethylamino-3,7-dihydro-3-propyl-2-thio- 238-2392H-purin-2-one 8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3,7-247-249 dihydro-2-thio-2H-purin-2-one3-benzyl-6-ethylamino-3,7-dihydro-2-thio-2H-purin-2- 254-257 one8-cyclopropyl-6-cyclopropylamino-3-propyl-3,7-dihydro- 208-2262-thio-2H-purin-2-one hydrochloride dec3-((2-methyl)butyl))-6-(2-(piperazine-1-yl)ethylamino)-3,7-dihydro-2-thio-2H-purin-2-one3-cyclohexylmethyl-3,7-dihydro-6-ethylamino-2-thio-2H- 295-300purin-2-one 3-benzyl-6-ethylamino-3,7-dihydro-8-(1-methylethyl)-2-thio-2H-purin-2-one3-cyclohexylmethyl-8-cyclopropyl-3,7-dihydro-6-ethyl- 278-282amino-2-thio-2H-purin-2-one6-benzylamino-8-(cyclopropyl)-3,7-dihydro-3-propyl-2- 180-185thio-2H-purin-2-one hydrochloride8-(cyclopropyl)-3,7-dihydro-6-hexylamino-3-(propyl)-2- 170-190thio-2H-purin-2-one hydrochloride6-butylamino-8-cyclopropyl-3,7-dihydro-3-propyl-2-thio- 231-2332H-purin-2-one 6-cyclopropyl-3,7-dihydro-6-(2-hydroxyethylamino)-2-188-192 thio-2H-purin-2-one6-amino-8-cyclopropyl-3,7-dihydro-3-propyl-2-thio-2H- 220-265purin-2-one 6-cyclopentylamino-3-ethyl-3,7-dihydro-8-isopropyl-2-301-304 thio-2H-purin-2-one6-cyclohexylamino-3,7-dihydro-8-isopropyl-3-propyl-2- 303 decthio-2H-purin-2-one6-cyclopentylamino-3,7-dihydro-8-isopropyl-3-propyl-2- 295 decthio-2H-purin-2-one6-cyclopentylamino-3-ethyl-8-cyclopropyl-3,7-dihydro-2- 245 decthio-2H-purin-2-one 3-(4-chlorobenzyl)-6-cyclopentylamino-3,7-dihydro-8-244-248 isopropyl-2-thio-2H-purin-2-one6-cyclopentylamino-3-(3-cyclopentyl-4-methoxybenzyl)- 230-2353,7-dihydro-8-isopropyl-2-thio-2H-purin-2-one3-(2-chlorobenzyl)-6-cyclopentylamino-3,7-dihydro-8-isopropyl-2-thio-purin-2-one8-cyclopropyl-3,7-dihydro-6-(3-pentyl)-3-propyl-2-thio- 220 dec2H-purin-2-one 6-ethyl-8-isopropyl-3,7-dihydro-3-(4-pyridylmethyl)-2-238-40 thio-2H-purin-2-one

EXAMPLE 18 Elemental Analysis of Thiosoguanine Derivates

A. Elemental analysis for6-butylamino-8-cyclo-propyl-3,7-dihydro-3-propyl-2H-purine-2-thione:

Calc. C 58.98 H 7.59 N 22.93 Found C 58.99 H 7.52 N 22.92

B.3-(cyclopropylmethyl)-3,7-dihydro-8-isopropyl-6-propylamino-2H-purine-2-thione;

Melting point: 208-210° C.;

Elemental analysis:

Calc. C 62.26 H 8.01 N 24.20 Found C 62.34 H 8.06 N 23.89

EXAMPLE 19 PDE IV Inhibition by Thioisoguanine Compounds

The PDE IV inhibitory activity of certain of the foregoingthioisoguanine compounds was determined according to the procedures setforth below. The results are provided in Table 2.

Type IV Phosphodiesterase Enzyme Isolation Protocol

The Type IV PDE is isolated from bovine tracheal smooth muscle using aprocedure similar to that previously described by Silver, P. J., Hamel,L. T., Perrone, M. H. Bentley, R. G. Bushover, C. R., Evans, D. B.: Eur.J. Pharmacol. 150:85,1988.(1). Briefly, smooth muscle from bovinetrachea is minced and homogenized using a polytron in 10 volumes of anextraction buffer containinhg 10 mM Tris-acetate (pH 7.5), 2 mMmagnesium chloride, 1 mM dithiothreitol and 2,000 units/ml of aprotinin.This and all subsequent procedures are performed at 0-4° C. Thehomogenate is sonicated and then centrifiged at 48,000×g for 30 minutes.The resulting supernatant is applied to a DEAE Trisacryl M columnpreviously equilibrated with sodium acetate and dithiothreitol. Afterapplications of the sample, the column is washed with sodiumacetate/dithiothreitol, after which the different forms of PDE areeluted from the column using a linear Tris-HCl/NaCl gradient. Fractionscontaining Type IV PDE are collected, dialyzed and concentrated to 14%of the original volume. The concentrated fractions are diluted to 50%with ethylene glycol and stored at -20° C.

Measuring Type IV PDE Activity

Enzyme activity is assessed by measuring the hydrolysis of [³H]-cyclicAMP, as described by Thompson, W. J., Teraski, W. L., Epstein, P. N.,Strada, S. J.: Adv. Cyclic Nucleotide Res. 10:69, 1979. The cyclic AMPconcentration used in this assay is 0.2 μM, which approximates the K_(m)value. Protein concentration is adjusted to ensure that no more than 15%of the available substrate is hydrolyzed during the incubation period.

All test compounds are dissolved in dimethyl sulfoxide (finalconcentration of 2.5%). This concentration of dimethyl sulfoxideinhibits enzyme activity by approximately 10%.

TABLE 2 THIOISOGUANINES - BIOLOGICAL DATA Calc IC50 Name PDE IV3-(cyclopropylmethyl)-3,7-dihydro-8-(1-methyl- 23.95ethyl)-6-propylamino-2-thio-2H-purin-2-one hydrochloride8-cyclopropyl-3-ethyl-6-ethylamino-3,7-dihydro-2- 13.65thio-2H-purin-2-one 8-cyclopropyl-3-ethyl-6-propylamino-2-thio-2H- 8.48purin-2-one 3-butyl-8-cyclopropyl-3,7-dihydro-6-ethylamino-2- 34.86thio-2H-purin-2-one 3-benzyl-6-ethylamino-3,7-dihydro-8-(1-methyl- 28.37ethyl)-2-thio-2H-purin-2-one3-cyclohexylmethyl-8-cyclopropyl-3,7-dihydro-6- 15.20ethylamino-2-thio-2H-purin-2-one6-benzylamino-8-(cyclopropyl)-3,7-dihydro-3-propyl- 33.602-thio-2H-purin-2-one hydrochloride8-cyclopropyl-3,7-dihydro-3-propyl-6-(4-pyridyl- 0.41methylamino)-2-thio-2H-purin-2-one6-cyclopentylamino-8-cyclopropyl-3,7-dihydro-3- 7.41propyl-2-thio-2H-purin-2-one hydrochloride6-butylamino-8-cyclopropyl-3,7-dihydro-3-propyl-2- 24.48thio-2H-purin-2-one 8-cyclopropyl-3,7-dihydro-6-(2-hydroxyethylamino)-53.80 3-propyl-2-thio-2H-purin-2-one 6-amino-8-cyclopropyl-3,7-dihydro-3propyl-2-thio- 39.42 2H-purin-2-one3-ethyl-6-cyclopentylamino-3,7-dihydro-8-isopropyl- 9.402-thio-2H-purin-2-one 6-cyclopentylamino-3,7-dihydro-8-isopropyl-3-45.10 propyl-2-thio-2H-purin-2-one3-ethyl-6-cyclopentylamino-8-cyclopropyl-3,7- 0.19dihydro-2-thio-2H-purin-2-one3-(4-chlorobenzyl)-6-cyclopentylamino-3,7-dihydro- 114.508-isopropyl-2-thio-2H-purin-2-one

EXAMPLE 20 Adenine Derivates

Following the method of the above Examples, the following compounds weresimilarly prepared from the appropriate starting materials. Alltemperatures are in ° C. unless otherwise stated.

The data is provided in Table 3 below.

TABLE 3 ADENINES Compound m.p. 6-ethylamino-3-hexyl-3H-purinehydrochloride 190-195 3-hexyl-6-methylamino-3H-purine 142-38-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine 188-190hydrochloride 8-cyclopropyl-3-ethyl-6-propylamino-3H-purine 186-188hydrochloride 8-cyclopropyl-3-ethyl-6-methylamino-3H-purine 143-1453-butyl-6-ethylamino-3H-purine 127-1293-butyl-8-cyclopropyl-6-ethylamino-3H-purine 182-1846-ethylamino-3-propyl-3H-purine 157-1598-cyclopropyl-6-ethylamino-3-propyl-3H-purine 193-195 hydrochloride8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H 195-197 purinehydrochloride 3-benzyl-6-ethylamino-3H-purine 187-1888-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine hydrochloride200-210 3-(2-methylbutyl)-6-(2-(piperazin- 144-1451-yl)ethylamino)-3H-purine 3-cyclohexylmethyl-6-ethylamino-3H-purine258-265 hydrochloride 3-benzyl-6-ethylamino-8-(1-methylethyl)-3H-purine199-200 hydrochloride 3-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-192-193 purine hydrochloride3-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine  96-993-ethyl-8-isopropyl-6-benzylamino-3H-purine 141-1423-ethyl-8-isopropyl-6-ethylamino-3H-purine 194-195 hydrochloride3-ethyl-8-cyclopentyl-6-benzylamino-3H-purine 179-182 hydrochloride3-ethyl-8-cyclopentyl-6-ethylamino-3H-purine 212-214 hydrochloride3-(4-chlorobenzyl)-6-ethylamino-3H-purine3-(4-chlorobenzyl)-6-ethylamino-3H-purine hydrochloride 251-43-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine3-(4-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine 215-7hydrochloride 6-benzylamino-8-cyclopropyl-3-propyl-3H-purine 153-558-cyclopropyl-6-hexylamino-3-propyl-3H-purine 137-8 hydrochloride8-cyclopropyl-3-propyl-6-(4-pyridylmethylamino)-3H- 185-208 purinedihydrochloride 6-cyclopentylamino-8-cylopropyl-3-propyl-3H-purine 273-6hydrochloride 6-butylamino-8-cyclopropyl-3-propyl-3H-purine 171-3hydrochloride 8-cyclopropyl-6-(2-hydroxyethylamino)-3-propyl-3H- 217-9purine 6-(3-cyclopentyloxy-4-methoxybenzylamino)-8-cyclopropyl-3-propyl-3H-purine hydrochloride6-amino-8-cyclopropyl-3-propyl-3H-purine 188-903-ethyl-6-cyclopentylamino-8-isopropyl-3H-purine 183-4 hydrochloride6-cyclohexylamino-8-isopropyl-3-propyl-3H-purine 202-3 hydrochloride6-cyclopentylamino-8-isopropyl-3-propyl-3H-purine 207-10 hydrochloride3-ethyl-6-cyclopentylamino-8-cyclopropyl-3H-purine 205-8 hydrochloride3-(4-chlorobenzyl)-6-cyclopentylamino-8-cyclopropyl- 269-73 3H-purinehydrochloride 6-cyclopentylamino-3-(3-cyclopentyloxy-4-methoxy- 193-5benzyl)-8-isopropyl-3H-purine hydrochloride3-(2-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H- 207-8 purinehydrochloride 8-cyclopropyl-6-diethylamino-3-propyl-3H-purine 173-9hydrochloride 8-cyclopropyl-6-(3-pentylamino)-3-propyl-3H-purine 187-9hydrochloride 6-ethylamino-8-isopropyl-3-(4-pyridylmethyl)-3H-purine240-6 dihydrochloride

EXAMPLE 21 Elemental Analysis of Adenines

Elemental analysis was conducted for certain of the compounds set forthin the above tables. The results are provided below.

Elemental analysis for 8-cyclopropyl-3- ethyl-6-ethylamino-3H-purinehydrochloride 99% + 1% (H₂O, HCl) Calc. C 53.29 H 6.80 N 25.90 O 0.53Found C 52.97 H 7.01 N 26.01 O 0.34 Elemental analysis for 6-ethyl-amino-3-hexyl-3H-purine hydrochloride mp 188-94° Calc. C 55.02 H 7.81 N24.68 Cl 12.49 Found C 55.33 H 8.05 N 24.50 Cl 12.71 Elemental analysisfor 3-hexyl- 6-methylamino-3H-purine hydrochloride mp 190-195° Calc. C53.43 H 7.47 N 25.96 Cl 13.14 Found C 53.70 H 7.81 N 25.92 Cl 13.18Elemental analysis for 8-cyclopropyl-6-ethyl-amino-3-(3-methylbutyl)-3H-purine hydrochloride Calc. C 58.15 H 7.81 N22.60 Cl 11.44 Found C 58.12 H 8.01 N 22.65 Cl 11.46 Elemental analysisfor 8-cyclopropyl-3- ethyl-6-propylamino-3H-purine hydrochloride Calc. C55.41 H 7.15 N 24.85 Cl 12.58 Found C 55.74 H 7.06 N 25.08 Cl 12.71Elemental analysis for 8-cyclo- propyl-3-ethyl-6-methylamino-3H-purineCalc. C 60.81 H 6.96 N 32.23 Found C 60.58 H 7.02 N 32.67 Elementalanalysis for 3-butyl-6- ethylamino-3H-purine hydrochloride mp 221-223°Calc. C 51.65 H 7.09 N 27.38 Cl 13.88 Found C 51.74 H 7.06 N 27.62 Cl13.93 Elemental analysis for 3-butyl-8-cyclopropyl-6-ethylamino-3H-purine hydrochloride mp 194-196° Calc. C 56.83 H 7.49 N23.67 Cl 11.98 Found C 56.91 H 6.98 N 23.97 Cl 12.03 Elemental analysisfor 6-ethyl- amino-3-propyl-3H-purine 98% + 2% water Calc. C 57.35 H7.44 N 33.44 Found C 57.68 H 7.22 N 33.29 Elemental analysis for8-cyclopropyl-6- ethylamino-3-propyl-3H-purine hydrochloride Calc. C55.41 H 7.15 N 24.85 Cl 12.58 Found C 55.45 H 7.13 N 24.96 Cl 12.71Elemental analysis for 8-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine hydrochloride Calc. C 57.23 H6.87 N 23.84 Cl 12.07 Found C 57.49 H 6.88 N 23.59 Cl 12.49 Elementalanalysis for 3-benzyl-6-ethylamino-3H-purine Calc. C 66.39 H 5.97 N27.65 Found C 66.58 H 5.63 N 27.80 Elemental analysis for8-cyclopropyl-6- cyclopropylamino-3-propyl-3H-purine hydrochloride Calc.C 57.23 H 6.86 N 23.84 Cl 12.07 Found C 57.30 H 6.90 N 23.77 Cl 12.16Elemental analysis for 3-cyclohexylmethyl- 6-ethylamino-3H-purinehydrochloride Calc. C 56.84 H 7.50 N 23.67 Cl 11.98 Found C 56.82 H 7.54N 23.65 Cl 12.05 Elemental analysis for 3-benzyl-6-ethylamino-8-(1-methylethyl)-3H-purine hydrochloride Calc. C 61.52 H6.68 N 21.10 Cl 10.68 Found C 61.52 H 6.59 N 21.18 Cl 10.60 Elementalanalysis for 3-cyclohexylmethyl-8- cyclopropyl-6-ethylamino-3H-purinehydrochloride Calc. C 60.79 H 7.80 N 20.85 Cl 10.56 Found C 60.55 H 7.48N 20.85 Cl 11.34 Elemental analysis for 3-cyclopropyl-methyl-8-isopropyl-6-ethylamino-3H-purine Calc. C 64.84 H 8.16 N 27.00Found C 64.42 H 7.86 N 26.87 Elemental analysis for 6-benzylamino-3-ethyl-8-isopropyl-6-ethylamino-3H-purine Calc. C 69.12 H 7.17 N 23.71Found C 69.27 H 7.44 N 23.60 Elemental analysis for 3-ethyl-8-isopropyl-6-ethylamino-3H-purine hydrochloride Calc. C 53.43 H 7.47 N25.96 Found C 53.62 H 7.66 N 25.34 Elemental analysis for6-benzylamino-8- cyclopentyl-3-ethyl-3H-purine hydrochloride Calc. C63.78 H 6.76 N 19.57 Found C 63.55 H 6.54 N 19.51 Elemental analysis for8-cyclopentyl-3- ethyl-6-ethylamino-3H-purine hydrochloride Calc. C56.84 H 7.50 N 23.67 Found C 56.54 H 7.37 N 23.63

EXAMPLE 22 PDE IV Inhibition by Adenine Compounds

The PDE IV inhibitory effect of certain of the compounds set forth abovewas examined according to the methods previously described. The resultsare provided in Table 4 below.

TABLE 4 PDE IV RESULTS calc PDE IV Compound IC50 (μM)3-ethyl-8-isopropyl-6-ethylamino-3H-purine hydrochloride 52.173-ethyl-8-cyclopentyl-6-benzylamino-3H-purine hydrochloride 62.443-ethyl-8-cyclopentyl-6-ethylamino-3H-purine hydrochloride 28.343-cyclohexylmethyl-6-ethylamino-3H-purine hydrochloride 32.953-cyclohexylmethyl-8-cyclopropyl-6-ethylamino-3H-purine 3.78hydrochloride 8-cyclopropyl-6-ethylamino-3-(3-methylbutyl)-3H-purine2.45 hydrochloride 8-cyclopropyl-3-ethyl-6-propylamino-3H-purinehydrochloride 15.678-cyclopropyl-3-cyclopropylmethyl-6-ethylamino-3H-purine 4.11hydrochloride 3-hexyl-6-methylamino-3H-purine hydrochloride 34.153-cyclopropylmethyl-8-isopropyl-6-ethylamino-3H-purine 12.66hydrochloride 3-ethyl-8-isopropyl-6-benzylamino-3H-purine hydrochloride28.94 3-butyl-6-ethylamino-3H-purine hydrochloride 66.413-butyl-8-cyclopropyl-6-ethylamino-3H-purine hydrochloride 5.998-cyclopropyl-6-ethylamino-3-propyl-3H-purine hydrochloride 6.318-cyclopropyl-6-cyclopropylamino-3-propyl-3H-purine 7.90 hydrochloride3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-iso- 0.32propyl-3H-purine hydrochloride 3-(4-chlorobenzyl)-6-ethylamino-3H-purinehydrochloride 37.753-ethyl-6-ethylamino-8-((3-cyclopentyloxy-4-methoxy)benzyl)- 4.523H-purine hydrochloride

EXAMPLE 23

Dithioxanthine derivatives of the present invention were manufacturedand analyzed. The results are set forth in Table 5 below.

TABLE 5 DITHIOXANTHINES IC50 PDE Compound m.p. IV3,7-dihydro-3-ethyl-2,6-dithio-1H- 275-276 purine-2,6-dione3,7-dihydro-3-propyl-2,6-dithio-1H- 294-297 purine-2,6-dione3,7-dihydro-8-ethyl-3-propyl-2,6- 266-267 dithio-1H-purine-2,6-doine3-butyl-3,7-dihydro-2,6-dithio-1H- 249-251 purine-2,6-dione3-butyl-3,7-dihydro-8-ethyl-2,6-dithio- 251-252 1H-purine-2,6-dione3,7-dihydro-3,8-diethyl-2,6-dithio-1H- 260-261 purine-2,6-dione3-benzyl-3,7-dihydro-2,6-dithio-1H- 298-303 38.49 purine-2,6-dione3,7-dihydro-3-hexyl-2,6-dithio-1H- 222-224 purine-2,6-dione8-cyclopropyl-3,7-dihydro-3-(3- 6.31methylbutyl)-2,6-dithio-1H-purine-2,6- dione8-cyclopropyl-3,7-dihydro-3-ethyl-2,6- 6.18 dithio-1H-purine-2,6-dione3,7-dihydro-3-(2-methylbutyl)-2,6- 263-4 dithio-1H-purine-2,6-dione3-butyl-8-cyclopropyl-3,7-dihydro-2,6- 9.43 dithio-1H-purine-2,6-dione3-cyclopropylmethyl-3,7-dihydro-2,6- 276-8 dithio-1H-purine-2,6-dione8-cyclopropyl-3,7-dihydro-3-propyl- 64.49 2,6-dithio-1H-purine-2,6-dione8-cyclopropyl-3-cyclopropylmethyl-3,7- 2.27dihydro-2,6-dithio-1H-purine-2,6-dione3-butyl-3,7-dihydro-8-(1-methylethyl)- 5.932,6-dithio-1H-purine-2,6-dione 3-cyclohexylmethyl-3,7-dihydro-2,6- 292-4dithio-1H-purine-2,6-dione 3-benzyl-3,7-dihydro-8-(1- 3.40methylethyl)-2,6-dithio-1H-purine-2,6- dione3-cyclohexylmethyl-8-cyclopropyl-3,7- 3.03dihydro-2,6-dithio-1H-purine-2,6-dione3-(3-cyclopentyloxy-4-methoxybenzyl)- 204-206 0.603,7-dihydro-8-isopropyl-2,6-dithio-1H- purine-2,6-dione3-(3-cyclopentyloxy-4-methoxybenzyl)- 215-218 16.163,7-dihydro-2,6-dithio-1H-purine-2,6- dione3-(4-chlorobenzyl)-8-isopropyl)-3,7 242-243 2.40dihydro-2,6-dithio-3,7-purine-2,6-dione3-ethyl-3,7-dihydro-8-isopropyl-2,6- 248-250 4.10dithio-1H-purine-2,6-dione 3,7-dihydro-8-isopropyl-3-propyl-2,6- 2033.50 dithio-1H-purine-2,6-dione 3-(2-chlorobenzyl)-3,7-dihydro-8-244-246 7.74 isopropyl-2,6-dithio-1H-purine-2,6- dione8-isopropyl-3-(4-pyridylmethyl)-2,6- 310-315 dithio-1H-purine-2,6-dione

EXAMPLE 24 Pharmacologial Tests Isolated Guinea Pig Trachea

The test compound was dissolved in dimethylsulfoxide. Guinea pigisolated trachealis muscle was mounted in a bath containing Krebssolution maintained at 37.5° C. and bubbled with carbogen (95% 02, 5%CO₂).

Tension changes were recorded isometrically using force displacementtransducers in conjunction with potentiometric pen recorders.

The ability of the test compounds to relax airways muscle wasinvestigated by the construction of cumulative concentration effectcurves. Each concentration of the test compound was allowed toequilibrate with the tissue for 5 minutes before a concentrationincrement (ten-fold) was made.

In each tissue the test compound was compared with theophylline asstandard.

Compound In Vitro Activity Theophylline 18-Cyclopropyl-3-ethyl-6-ethylamino-3H-purine 43.76-Ethylamino-3-hexyl-3H-purine 25.6 3-Benzyl-6-ethylamino-3H-purine 18.5

EXAMPLE 25 In-vivo Studies

(i) The effect of test compounds in a model of bronchialhyperresponsiveness (BHR) and cellular infiltration in the guinea piginduced by ovalbumin (see, for example Morley et al, Agents and Actions,Supplement, 1988, 23, 187) were studied.

The test compound was administered at doses of 0.5 and 1.0 mg/kg/daygiven subcutaneously over 7 days by osmotic mini-pump. Theophylline andsalbutamol at concen-trations of 1 mg/kg/day were used as standards.Dose response curves to histamine (1-50 μg/kg) were constructed for eachanimal.

FIGS. 1-2 show the results obtained.

(ii) Sensitization and Challenge procedure: Male Dunkin Hartley guinepigs (Charles River) (200-250 g) were injected i.p. with ovalbumin (OVA)(0.5 ml/animal; 20 μg OVA in AlOH)₃ (moist gel)); this preparationproduced an injectable stable suspension containing excess Al(OH)₃. Shamanimals were injected with 0.5 ml Al(OH)₃ alone. After a period of 18-21days animals were exposed to an aerosol of OVA (100 μg/ml) for 1 hour inan exposure chamber.

(iii) Bronchoalveloar lavage: Animals were anaesthetized, 24 hours afteraerosol exposure, with urethane (25%, w/v, 7 ml/kg, i.p.) and thetrachea cannulated. Bronchoalveo-lar lavage (BAL) was performed byinstilling 5 ml sterile saline into the lungs via the tracheal cannulaand the fluid was immediately removed. The fluid was reinjected and theprocedure repeated 5 times in total. This procedure resulted in a 40-60%recovery of BAL fluid from the lungs of the guinea pig. Total cellcounts were perfomed on the resultant BAL fluid using an improvedNeubauer haemocytometer. Cytospin preparations were prepared using aShandon Cytospin 2 centrifuge. Two drops of BAL fluid were added to eachcytospin cup and the samples were centrifuged for 1 min at 1300 r.p.m.Slides were fixed in acetone and stained with haemotoxylin and carbolchromotrope according to the method described by Lendrum (Lendrum 1944),differential cell counts were performed on each slide by counting 200cells at random, the cell types were classified as neutrophils,eosinophils and mononuclear cells according to standard morphologicalcriteria. Cells were counted blind. The results are expressed as thenumber of neutrophils, eosinophils and mononuclear cells per ml of BALfluid. The remaining BAL fluid was centrifuged (10 min., 1000 g) and theresultant cells and cell free supernatants were aliquotted and frozenfor later assays. Compounds were solu-bilized in either DMSO or salineadministered intraperitoreally at a dose of 5 mg/kg one hour prior toovalbumin challenge. The results are provided below in Table 6.

TABLE 6 Dose mg/kg % Eosinophils Compound N ip in BAL x ± se %Inhibition DMSO Vehicle 9 — 32 ± 6 — 3-(3-cyclo- 6 5 17 ± 3 47%pentyloxy-4- methoxybenzyl)- 3,7-dihydro-8-iso- propyl-2,6-dithio-1H-purin-2,6-dione Saline Vehicle 14 — 33 ± 3 — 8-cyclopropyl-6- 7 5 16± 4 52% ethylamino-3-(3- methylbutyl)-3H- purine hydro- chloride3-(3-cyclopentyl- 7 5 12 ± 2 64% oxy-4-methoxy- benzyl)-6- ethylamino-8-isopropyl-3H- purine hydro- chloride

EXAMPLE 26 Synthesis and Assay of Adenine Compounds

Following the previously set forth methods, the following adeninederivatives of the present invention were synthesized and assayed forPDE IV inhibition activity as provided in Table 7 below.

TABLE 7 PDE IV RESULTS calc PDE IV Compound IC50 (μM)6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1- .091methylethenyl)-3H-purine;6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy- .052benzyl)-3H-purine; 6-amino-8-[(1-benzyloxy-1-methyl)ethyl]-3-[(3- .005cyclopentyloxy-4-methoxy)benzyl]-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-[1-(4- .034fluorobenzyloxy)-1-methyl-ethyl]-3H-purine;[8-(1-benzyloxy-1-methyl)ethyl]3-[(3-cyclopentyloxy-4- .85methoxy)benzyl]-6-ethylamino-3H-purine;6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy- .45benzyl)-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-[(1- .85hydroxy-1-methyl)ethyl]-3H-purine;6-Ethylamino-3-(3-butoxy-4-methoxy-benzyl)-8-isopropyl-3H 1.4 purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1- .25hydroxy-1-methyl)ethyl]-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-(1- .27methyl-ethenyl)-3H-purine;6-ethylamino-2-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine; .316-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-3H-purine; .313-(3-cyclopentyloxy-4-methoxybenzyl)-6-dimethylamino-8- 19.3isopropyl-3H-purine; 6-Ethylamino-3-[3-(3-hydroxycyclopentyloxy)-4- 2.6methoxybenzyl)]-8-(1-hydroxy-1-methylethyl)-3H-purine;6-ethylamino-3-(3-,4-methylenedioxybenzyl)-8-isopropyl-3H- .44 purine;6-ethylamino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8- .66isopropyl-3H-purine;3-(3-benzyloxy-4-methoxy-benzyl)-6-ethylamino-8-isopropyl- 1.33H-purine; 6-Amino-3-(3,4-dimethoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-1.85 methylethyl]-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-amino-8-isopropyl- .82 3H-purine;6-(amino-8-(1-benzyloxy-1-methylethyl)-3-(3,4- .94dimethoxybenzyl)-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(3-cyclopentyloxy-4- 1.14methoxybenzylamino)-8-isopropyl-3H-purine;6-ethylamino-8-isopropyl-3-(4-methoxybenzyl)-3H-purine; 1.23-(3-((3-hydroxy)cyclopentyloxy)-4-methoxybenzyl)-6- 1.36ethylamino-8-isopropyl-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-(N-benzoyl-N- 1.43ethylamino)-8-isopropyl-3H-purine;3-(4-chlorobenzyl)-6-cyclopropylamino-8-isopropyl-3H-purine; 1.696-ethylamino-8-isopropyl-3-[(4-methoxy-3-(4- 1.75hydroxybutoxy))benzyl]-3H-purine;6-ethylamino-3-(4-fluorobenzyl)-8-isopropyl-3H-purine; 1.853-(3-chlorobenzyl)-6-ethylamino-8-isopropyl-3H-purine; 2.153-[3-(3-Hydroxy-cyclopentyloxy)-4-methoxy-benzyl]-8-(1- 2.25hydroxy-1-methyl-ethyl)-3H-purine;3-[3-(3-hydroxy)cyclopentyloxy)]-4-methoxy)benzyl)-6- 2.28ethylamino-8-isopropyl-3H-purine;6-amino-3-(3,4-dimethoxybenzyl)-8-isopropyl-3H-purine; .926-Ethylamino-3-[3-cyclopentylmethoxy-4-methoxy-benzyl]-8- 12.5isopropyl-3H-purine;6-ethylamino-3-(3-hydroxy-4-methoxybenzyl)-8-isopropyl-3H- 2.73 purine;6-Ethylamino-3-[3-(2,2-dimethylaminoethoxy-4-methoxy)]-8- 8.95isopropyl-3H-purine;3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-methyl-1- 3.1hydroxy)ethyl]-6-ethylamino-3H-purine;6-amino-3-[(3-benzyloxy-4-methoxy)benzyl]-8-[(1-benzyloxy- 3.121-methyl)ethyl]-3H-purine;3-(3-cyclopentyloxy-4-methoxybenzyl)-6-((2,2,2- 12.8trifluoroethyl)amino)-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(2,2,2)-azabicyclooctan-3-yloxy)-4- 2.05methoxy]-8-isopropyl-3H-purine;6-Ethylamino-3-[3-(1-methylpiperidin-4-yl-methoxy)-4- 6.6methoxy-benzy]-8-isopropyl-3H-purine;6-Amino-3-(3,4-dimethyoxybenzyl)-8-(1-methylethenyl)-3H- 3.7 purine;6-amino-8-isopropyl-3-[(4-methoxy-3-([(4- 4.2hydroxybutoxy))benzyl]-3H-purine;3-{2-(4-chlorophenyl)-ethyl]-6-ethylamino-8-isopropyl-3H- 4.46 purine;3-(4-chlorobenzyl)-6-((1-hydroxy)cyclopentylamino)-8- 4.48isopropyl-3H-purine;3-(4-chlorobenzyl)-6-cyclopentylamino-8-isopropyl-3H-purine, 4.76-amino-3(3,4-methylenedioxybenzyl)-8-isopropyl-3H-purine; 4.16-Ethylamino-3-[(exo-8-methyl-8-azabicyclo(3,2,1)-octan-3-yl- 6.02oxy)-4-methoxy-benzy]-8-isopropyl-3-H-purine;6-amino-3-((3-benzyloxy-4-methoxy)-bezyl)-8-isopropyl-3H- 6.4 purine;3-(4-chlorophenyl)-6-ethylamino-8-isopropyl-3H-purine; 6.56-ethylamino-3-[(3-hydroxy-4-methoxy)benzyl]-8-[(1-hydroxy- 6.51-methyl)ethyl]- -3H-purine;6-Ethylamino-3-[(3-pyridin-4-yl-methoxy)N-oxide-4- 4.5methoxy]-8-isopropyl-3H-purine;3-[3-Cyclohexanyl-4-oxy-4-methoxy-benzyl]-6-ethylamino-8- 8.28isopropyl-3H-purine;3-(4-chlorobenzyl)-2,6-di(ethylamino)-8-isopropyl-3H-purine; 11.26-amino-3-(3-hydroxy-4-methoxy)-benzyl)-8-isopropyl-3H- 15.1 purine;6-amino-3-[3-(4-hydroxybutoxy-4-methoxy)benzyl]-8-(1- 17.1hydroxy-1-methylethyl)-3H-purine hydrochloride;6-amino-3-(4-chlorobenzyl)-8-isopropyl-3H-purine; 20.86-amino-3-cyclopentylmethyl-8-isopropyl-3H-purine; 23.28-cyclopropyl-3-ethyl-6-ethylamino-3H-purine; 27.16-Ethylamino-8-isopropyl-3-[3-(pyridin-4-yl-methoxy)-4- 24.5methoxy-benzyl]-3H-purine;6-Ethylamino-3-(1-oxopyridin-4-yl-methyl)-8-isopropyl-3H- 385 purine;and 6-amino-3-[(3-hydroxy-4-methoxy)benzyl)]]-8-[(1-hydroxy-1- 71000methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2- 38methoxy)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3- 30methoxy)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3,4-dimethoxy)benzyl]-8-[(1-(4- 20methyl)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(4- 25chloro)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2- 45fluoro)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3- 60fluoro)benzyloxy-1-methyl)ethyl]-3H-purine6-(3-fluoro)benzyloxyamino-3-[(3-cyclopentyloxy-4- 122methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]- 3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,5- 44dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4- 92dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4- 49fluoro)benzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3,4- 35methylenedioxybenzyloxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(2- 53thienylmethoxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3- 83thienylmethoxy-1-methyl)ethyl]-3H-purine6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(1- 109oxo-octyl)amino-1-methyl)ethyl]-3H-purine6-amino-3-(3,4-methylenedioxybenzyl)-8-[1-(4- .72fluorobenzyloxy)-1-methyl-ethyl]-3H-purine6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy- .17benzyl)-3H-purine;

While the invention has been illustrated with respect to the productionand use of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

What is claimed is:
 1. A compound of the formula (I):

and pharmaceutically acceptable salts thereof, wherein R³, R^(6a),R^(6b), and R⁸ is selected from the group consisting of A and B, whereinA is selected from the group consisting of hydrogen; C₁₋₁₀ alkyl whichis unbranched or branched and is optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen ═NOH, ═NOCONH₂, CO₂ H, ═O and benzyloxy; saidbenzyloxy optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxyand C₃₋₁₂ cycloalkoxy; C₂₋₁₀ alkenyl which is unbranched or branched andis optionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkyl which isoptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₀alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂,CO₂H and ═O; C₃₋₁₀ cycloalkenyl which is optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl,═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl wherein thecycloalkyl portion is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O; aryl which is optionally substituted with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, carbamyl, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀ alkysulfonylamino, phenyl andbenzyl; ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substitutedwith 1-3 substituents chosen from the group consisting of carboxy, C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀) alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy, C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy and C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy optionally substituted on acarbon with hydroxy and said heterocyclyl is optionally substituted withC₁₋₁₀ alkyl; and wherein the alkyl moiety of said ar (C₁₋₁₄)alkyl isoptionally substituted with OH, halogen, C₁₋₁₀ alkoxy or C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy being optionally substituted inone position at the alkyl moiety with hydroxy; heterocyclyl which isoptionally substituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, OH,halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀dialkylamino, amido, C₁₋₁₀ alkylamido, C₁₋₁₀ dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl and benzyl;heterocycly(C₄-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₂ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, carbamyl, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl andbenzyl, and wherein said alkyl moiety is optionally substituted with OH,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen orhalo(C₁₋₁₀)alkyl; heteroaryl, which is optionally substituted with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, halogen, nitro trihalocarbon, C₁₋₁₀ toalkoxy and C₃₋₁₂ cycloalkoxy; and B is selected from the groupconsisting of C₁₋₁₀ alkyl which is unbranched or branched and issubstituted with 1-3 substituents chosen from the group consisting ofbenzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl,pyridylmethoxy, thienylmethoxy and alkylamino; said substituentsoptionally substituted with 1-3 substituents chosen from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy and oxo; said substituted C₁₋₁₀ alkyl furtheroptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H, and ═O; C₂₋₃ or C₇₋₁₀ alkenyl which is unbranched orbranched and is optionally substituted with 1-3 substituents chosen fromthe group consisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkylwhich is substituted with 1-3 substituents chosen from the groupconsisting of C₂₋₁₀ alkyl and C₃₋₁₂ cycloalkyl; said substituted C₃₋₁₀cycloalkyl further optionally substituted with 1-3 substituents chosenfrom the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O; C₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl wherein thecycloalkyl portion is substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀ alkyl, and C₃₋₁₂ cycloalkyl; said substitutedC₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl further optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, ═NOH, ═NOCONH₂, and CO₂H; aryl which is substituted with1-3 substituents chosen from the group consisting of amido, C₁₋₁₀alkylamido, and C₁₋₁₀ dialkylamido; said substituted aryl furtheroptionally substitute with 1-3 substituents chosen from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl OH, halogen, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ akylamino, C₁₋₁₀ dialkylamino, phenyl andbenzyl; ar(C₁₋₄)alkyl wherein the aryl moiety is substituted with 1-3substituents chosen from the group consisting of carboxy, C₁₋₁₀alkylcarboxy, hydroxy(C₁₋₁₀)alkoxy, nitro, benzyloxy, heterocyclyl,C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy, ar(C₁₋₁₀)alkyloxy, aryloxy,amino(C₁₋₁₀)alkoxy, C₁₋₁₀ alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy,heteroar(C₁₋₁₀)alkyloxy, heterocyclyloxy, C₁₋₁₀ alkoxy and C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy substituted on a carbon withhydroxy and said heterocyclyl is optionally substituted with C₁₋₁₀ alkyland wherein the alkyl moiety of said ar (C₁₋₄)alkyl is optionallysubstituted with OH, halogen, C₁₋₁₀ alkoxy or C₃₋₁₂ cycloalkoxy; saidalkoxy and cycloalkoxy being optionally substituted in one position atthe alkyl moiety with hydroxy; and said substituted ar(C₁₋₄)alkylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, hydroxy, trihalocarbon, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; heterocyclyl which issubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of carbamyl, C₁₋₁₀acylamino and C₁₋₁₀ alkylsulfonylamino; said substituted heterocyclylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀ alkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀alkylamido, C₁₋₁₀ dialkylamido, phenyl and benzyl;heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is substitutedon the carbons or nitrogens of the ring with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino,and C₁₋₁₀ alkyl, said C₁₋₁₀ alkyl substituted with OH, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen or halo(C₁₋₁₀)alkyl; saidsubstituted heterocyclyl(C₁-C₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀ alkylamido and C₁₋₁₀dialkylamido; heteroaryl is optionally substituted with 1-3substitutents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is substituted withnitro; said heteroaryl(C₁₋₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, trihalocarbon, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy;and provided that at least one of R³, R^(6a), R^(6b) and R⁸ is B.
 2. Thecompound of claim 1 wherein R³ is A and is ar(C₁₋₄)alkyl wherein thearyl moiety is optionally substituted with 1-3 substituents chosen fromthe group consisting of halogen, nitro, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxyand CF₃, and wherein the alkyl moiety is optionally substituted with 1-3substituents chosen from the group consisting of OH, halogen, C₁₋₁₀alkoxy and C₃₋₁₂ cycloalkoxy.
 3. The compound of claim 2 wherein saidaralkyl is benzyl.
 4. The compound of claim 3 wherein the aryl moiety ofsaid benzyl is substituted with 1-3 substituents chosen from the groupconsisting of halogen, nitro, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy and CF₃.5. The compound of claim 4 wherein said benzyl is substituted withcyclopentyloxy and methoxy.
 6. The compound of claim 2 wherein R^(6a) isA and is hydrogen.
 7. The compound of claim 1 wherein R^(6b) is A and isselected from the group consisting of hydrogen; C₁₋₈ alkyl which isunbranched or branched and is optionally substituted with OH, alkoxy,cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H or ═O; and C₃₋₈ cycloalkylwhich is optionally substituted with OH, alkoxy, cycloalkoxy, halogen,haloalkyl, ═NOH, ═NOCONH₂, CO₂H or ═O.
 8. The compound of claim 1wherein R⁸ is B and is C₁₋₁₀ alkyl which is unbranched or branched andis substituted with 1-3 substituents chosen from the group consisting ofbenzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl,pyridylmethoxy, thienylmethoxy and alkylamino, said substituentsoptionally substituted with 1-3 substituents chosen from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy and oxo.
 9. A method for selectively effecting PDE IVinhibition, compared to PDE III inhibition, in a patient suffering froma disease state selected from the group consisting of inflammation,depression, Alzheimer's disease, vascular dementia, and multi-in-farctdemetia, said method comprising the administration of a compound of theformula (I):

and pharmaceutically acceptable salts thereof, wherein R³, R^(6a),R^(6b), and R⁸ is selected from the group consisting of A and B, whereinA is selected from the group consisting of hydrogen; C₁₋₁₀ alkyl whichis unbranched or branched and is optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen ═NOH, ═NOCONH₂, CO₂H, ↑O and benzyloxy; saidbenzyloxy optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxyand C₃₋₁₂ cycloalkoxy; C₂₋₁₀ alkenyl which is unbranched or branched andis optionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkyl which isoptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₁₋₁₀alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkenyl which is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O;C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion is optionallysubstituted with 1-3 substituents chosen from the group consisting ofOH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O; aryl which isoptionally substituted with 1-3 substituents chosen from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, carbamyl,amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀alkysulfonylamino, phenyl and benzyl; ar(C₁₋₄)alkyl wherein the arylmoiety is optionally substituted with 1-3 substituents chosen from thegroup consisting of carboxy, C₁₋₁₀ alkylcarboxy, halogen, hydroxy,hydroxy(C₁₋₁₀) alkoxy, nitro, trihalocarbon benzyloxy, heterocyclyl,C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy, ar(C₁₋₁₀)alkyloxy, aryloxy,amino(C₁₋₁₀)alkoxy, C₁₋₁₀ alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy,heteroar(C₁₋₁₀)alkyloxy, heterocyclyloxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; said alkoxy and cycloalkoxyoptionally substituted on a carbon with hydroxy and said heterocyclyl isoptionally substituted with C₁₋₁₀ alkyl; and wherein the alkyl moiety ofsaid ar (C₁₋₁₄)alkyl is optionally substituted with OH, halogen, C₁₋₁₀alkoxy or C₃₋₁₂ cycloalkoxy; said alkoxy and cycloalkoxy beingoptionally substituted in one position at the alkyl moiety with hydroxy;heterocyclyl which is optionally substituted on the carbons or nitrogensof the ring with 1-3 substituents chosen from the group consisting ofC₁₋₁₀ alkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl andbenzyl; heterocycly(C₁-C₄)alkyl wherein said heterocyclyl moiety isoptionally substituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, carbamyl, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl andbenzyl, and wherein said alkyl moiety is optionally substituted with OH,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen orhalo(C₁₋₁₀)alkyl; heteroaryl, which is optionally substituted with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, halogen, nitro trihalocarbon, C₁₋₁₀alkoxy and C₃₋₁₂ cycloalkoxy; and B is selected from the groupconsisting of C₁₋₁₀ alkyl which is unbranched or branched and issubstituted with 1-3 substituents chosen from the group consisting ofbenzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl,pyridylmethoxy, thienylmethoxy and alkylamino; said substituentsoptionally substituted with 1-3 substituents chosen from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy and oxo; said substituted C₁₋₁₀ alkyl furtheroptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkoxy, C₃-,₂ cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H, and ═O; C₂₋₁₀ alkenyl which is unbranched or branchedand is optionally substituted with 1-3 substituents chosen from thegroup consisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkylwhich is substituted with 1-3 substituents chosen from the groupconsisting of C₂₋₁₀ alkyl and C₃₋₁₂ cycloalkyl; said substituted C₃₋₁₀cycloalkyl further optionally substituted with 1-3 substituents chosenfrom the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀cycloalkenylwhich is optionally substituted with 1-3 substituents chosen from thegroup consisting of OH, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and═O; C₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl wherein the cycloalkyl portion issubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀ alkyl, and C₃₋₁₂ cycloalkyl; said substituted C₃₋₁₂cycloalkyl(C₁₋₁₀)alkyl further optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, ═NOH ═NOCONH₂, and CO₂H; aryl which is substituted with 1-3substituents chosen from the group consisting of amido, C₁₋₁₀alkylamido, and C₁₋₁₀ dialkylamido; said substituted aryl furtheroptionally substituted with 1-3 substituents chosen from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, phenyl andbenzyl; ar(C₁₋₄)alkyl wherein the aryl moiety is substituted with 1-3substituents chosen from the group consisting of carboxy, C₁₋₁₀alkylcarboxy, hydroxy(C₁₋₁₀)alkoxy, nitro, benzyloxy, heterocyclyl,C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy, ar(C₁₋₁₀)alkyloxy, aryloxy,amino(C₁₋₁₀)alkoxy, C₁₋₁₀ alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy,heteroar(C₁₋₁₀)alkyloxy, heterocyclyloxy, C₁₋₁₀ alkoxy and C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy substituted on a carbon withhydroxy and said heterocyclyl is optionally substituted with C₁₋₁₀ alkyland wherein the alkyl moiety of said ar(C₁₋₄)alkyl is optionallysubstituted with OH, halogen, C₁₋₁₀ alkoxy or C₃₋₁₂ cycloalkoxy; saidalkoxy and cycloalkoxy being optionally substituted in one position atthe alkyl moiety with hydroxy; and said substituted ar(C₁₋₄)alkylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, hydroxy, trihalocarbon, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; heterocyclyl which issubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of carbamyl, C₁₋₁₀acylamino and C₁₋₁₀ alkylsulfonylamino; said substituted heterocyclylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀ alkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀alkylamido, C₁₋₁₀ dialkylamido, phenyl and benzyl;heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is substitutedon the carbons or nitrogens of the ring with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀acylamino, C₁₋₁₀ alkylsulfonylamino,and C₁₋₁₀ alkyl, said C₁₋₁₀ alkyl substituted with OH, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen or halo(C₁₋₁₀)alkyl; saidsubstituted heterocyclyl(C₁-C₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀ alkylamido and C₁₋₁₀dialkylamido; heteroaryl is optionally substituted with 1-3substitutents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is substituted withnitro; said heteroaryl(C₁₋₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, trihalocarbon, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy;and provided that at least one of R³, R^(6a), R^(6b) and R⁸ is B.
 10. Apharmaceutical composition comprising a compound of the formula (I):

and pharmaceutically acceptable salts thereof, wherein R³, R^(6a),R^(6b), and R⁸ is selected from the group consisting of A and B, whereinA is selected from the group consisting of hydrogen; C₁₋₁₀ alkyl whichis unbranched or branched and is optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen ═NOH, ═NOCONH₂, CO₂H, ═O and benzyloxy; saidbenzyloxy optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxyand C₃₋₁₂ cycloalkoxy; C₂₋₁₀ alkenyl which is unbranched or branched andis optionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkyl which isoptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₀alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂,CO₂H and ═O; C₃₋₁₀ cycloalkenyl which is optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl,═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl wherein thecycloalkyl portion is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O; aryl which is optionally substituted with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, carbamyl, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀alkysulfonylamino, phenyl andbenzyl; ar(C₁₋₄)alkyl wherein the aryl moiety is optionally substitutedwith 1-3 substituents chosen from the group consisting of carboxy, C₁₋₁₀alkylcarboxy, halogen, hydroxy, hydroxy(C₁₋₁₀)alkoxy, nitro,trihalocarbon, benzyloxy, heterocyclyl, C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy,ar(C₁₋₁₀)alkyloxy, aryloxy, amino(C₁₋₁₀)alkoxy, C₁₋₁₀alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy, heteroar(C₁₋₁₀)alkyloxy,heterocyclyloxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy and C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy optionally substituted on acarbon with hydroxy and said heterocyclyl is optionally substituted withC₁₋₁₀ alkyl; and wherein the alkyl moiety of said ar(C₁₋₄)alkyl isoptionally substituted with OH, halogen, C₁₋₁₀ alkoxy or C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy being optionally substituted inone position at the alkyl moiety with hydroxy; heterocyclyl which isoptionally substituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, OH,halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀dialkylamino, amido, C₁₋₁₀ alkylamido, C₁₋₁₀ dialkylamido, C₁₋₁₀acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl and benzyl;heterocycly(C₁-C₄)alkyl wherein said heterocyclyl moiety is optionallysubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀C₁₋₁₀ dialkylamino, carbamyl, amido, C₁₋₁₀ alkylamido, C₁₋₁₀dialkylamido, C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino, phenyl andbenzyl, and wherein said alkyl moiety is optionally substituted with OH,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen orhalo(C₁₋₁₀)alkyl; heteroaryl, which is optionally substituted with 1-3substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is optionallysubstituted with 1-3 substituents chosen from the group consisting ofC₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, halogen, nitro trihalocarbon, C₁₋₁₀alkoxy and C₃₋₁₂ cycloalkoxy; and B is selected from the groupconsisting of C₁₋₁₀ alkyl which is unbranched or branched and issubstituted with 1-3 substituents chosen from the group consisting ofbenzyloxy, methylenedioxybenzyloxy, methyl enedioxyphenyl,pyridylmethoxy, thienylmethoxy and alkylamino; said substituentsoptionally substituted with 1-3 substituents chosen from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy and oxo; said substituted C₁₋₁₀ alkyl furtheroptionally substituted with 1-3 substituents chosen from the groupconsisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, ═NOH,═NOCONH₂, CO₂H, and ═O; C₂₋₁₀ alkenyl which is unbranched or branchedand is optionally substituted with 1-3 substituents chosen from thegroup consisting of OH, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, halogen, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀ cycloalkylwhich is substituted with 1-3 substituents chosen from the groupconsisting of C₂₋₁₀ alkyl and C₃₋₁₂ cycloalkyl; said substituted C₃₋₁₀cycloalkyl further optionally substituted with 1-3 substituents chosenfrom the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy,halogen halo(C₁₋₁₀)alkyl, ═NOH, ═NOCONH₂, CO₂H and ═O; C₃₋₁₀cycloalkenyl which is optionally substituted with 1-3 substituentschosen from the group consisting of OH, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, halogen, halo(C₁₋₁₀)alkyl, ═NOH,═NOCONH₂, CO₂H and ═O; C₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl wherein thecycloalkyl portion is substituted with 1-3, substituents chosen from thegroup consisting of C₁₋₁₀ alkyl, and C₃₋₁₂ cycloalkyl; said substitutedC₃₋₁₂ cycloalkyl(C₁₋₁₀)alkyl further optionally substituted with 1-3substituents chosen from the group consisting of OH, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, ═NOH, ═NOCONH₂, and CO₂H; aryl which is substituted with1-3 substituents chosen from the group consisting of amido, C₁₋₁₀alkylamido, and C₁₋₁₀ dialkylamido; said substituted aryl furtheroptionally substituted with 1-3 substituents chosen from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, phenyl andbenzyl; ar(C₁₋₄)alkyl wherein the aryl moiety is substituted with 1-3substituents chosen from the group consisting of carboxy, C₁₋₁₀alkylcarboxy, hydroxy(C₁₋₁₀)alkoxy, nitro, benzyloxy, heterocyclyl,C₁₋₁₀ cycloalkyl(C₃₋₁₂)alkyloxy, ar(C₁₋₁₀)alkyloxy, aryloxy,amino(C₁₋₁₀)alkoxy, C₁₋₁₀ alkylamino(C₁₋₁₀)alkoxy, heteroaryloxy,heteroar(C₁₋₁₀)alkyloxy, heterocyclyloxy, C₁₋₁₀ alkoxy and C₃₋₁₂cycloalkoxy; said alkoxy and cycloalkoxy substituted on a carbon withhydroxy and said heterocyclyl is optionally substituted with C₁₋₁₀ alkyland wherein the alkyl moiety of said ar (C₁₋₄)alkyl is optionallysubstituted with OH, halogen, C₁₋₁₀ alkoxy or C₃₋₁₂ cycloalkoxy; saidalkoxy and cycloalkoxy being optionally substituted in one position atthe alkyl moiety with hydroxy; and said substituted ar(C₁₋₄)alkylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of halogen, hydroxy, trihalocarbon, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; heterocyclyl which issubstituted on the carbons or nitrogens of the ring with 1-3substituents chosen from the group consisting of carbamyl, C₁₋₁₀acylamino and C₁₋₁₀ alkylsulfonylamino; said substituted heterocyclylfurther optionally substituted with 1-3 substituents chosen from thegroup consisting of C₁₋₁₀ alkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, NH₂, C₁₋₁₀ alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀alkylamido, C₁₋₁₀ dialkylamido, phenyl and benzyl;heterocyclyl(C₁-C₄)alkyl wherein said heterocyclyl moiety is substitutedon the carbons or nitrogens of the ring with 1-3 substituents chosenfrom the group consisting of C₁₋₁₀ acylamino, C₁₋₁₀ alkylsulfonylamino,and C₁₋₁₀ alkyl, said C₁₋₁₀ alkyl substituted with OH, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, C₃₋₁₂ cycloalkyl, halogen or halo(C₁₋₁₀)alkyl; saidsubstituted heterocyclyl(C₁-C₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, OH, halogen, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, NH₂, C₁₋₁₀alkylamino, C₁₋₁₀ dialkylamino, amido, C₁₋₁₀ alkylamido and C₁₋₁₀dialkylamido; heteroaryl is optionally substituted with 1-3substitutents chosen from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, halogen, nitro, CF₃, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy; andheteroaryl(C₁₋₄)alkyl, wherein the heteroaryl moiety is substituted withnitro; said heteroaryl(C₁₋₄)alkyl further optionally substituted with1-3 substituents chosen from the group consisting of C₁₋₁₀ alkyl C₃₋₁₂cycloalkyl, halogen, trihalocarbon, C₁₋₁₀ alkoxy and C₃₋₁₂ cycloalkoxy;and provided that at least one of R³, R^(6a), R^(6b) and R⁸ is B; and apharmaceutically acceptable excipient.
 11. A compound of claim 1selected from the group consisting of6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-methoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-methoxyl)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3,4dimethoxy)benzyl]-8-[(1-(4-methyl)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(4-chloro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(2-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,5-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-dimethoxy)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(3,4-fluoro)benzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3,4-methylenedioxybenzyloxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(2-thienylmethoxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(3-thienylmethoxy-1-methyl)ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[(1-(1-oxo-octyl)amino-1-methyl)ethyl]-3H-purine;amino-3-(3,4-methylenedioxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine;6-amino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-[1-(4-pyridylmethoxy)-1-methyl-ethyl]-3H-purine;6-ethylamino-3-(3-benzyloxy-4-methoxybenzyl)-8-isopropyl-3H-purine;3-[(3-benzyloxy-4-methoxy)benzyl-8-[(1-benzyloxy-1-methyl)-ethyl]-6-ethylamino-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-[1-(4-methoxybenzyloxy)-1-methyl-ethyl]-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-(1-methylethenyl)-3H-purine;6-Amino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine;6-amino-8-[(1-benzyloxy-1-methyl)ethyl]-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-3H-purine;6-Amino-3-(3-cyclopentyloxy-4-methoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methyl-ethyl]-3H-purine;8-[(1-benzyloxy-1-methyl)ethyl]-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-3H-purine;6-ethylamino-8-benzyloxymethyl-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine;6-ethylamino-3-(3,4-methylenedioxybenzyl)-8-isopropyl-3H-purine;6-Amino-3-(3,4-dimethoxybenzyl)-8-[1-(4-fluorobenzyloxy)-1-methylethyl]-3H-purine;6-amino-8-(1-benzyloxy-1-methylethyl)-3-(3,4-dimethoxybenzyl)-3H-purine;6-amino-3-[(3-benzyloxy-4-methoxy)benzyl]-8-[(1-benzyloxy-1-methyl)ethyl]-3H-purine;6-Amino-3-(3,4-dimethoxybenzyl)-8-(1-methylethenyl)-3H-purine;6-amino-3-((3-benzyloxy-4-methoxy)-benzyl)-8-isopropyl-3H-purine;3-(3-benzyloxy-4-nitro-benzyl)-6-ethylamino-8-isopropyl-3H-purine;3-[cyclopentyloxy-4-methoxy)benzyl]-6-ethylamino-8-(1-methyl-ethenyl)-3H-purine;and pharmaceutically acceptable salts thereof.